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                    review

Androgen insensitivity
syndrome: a review
Rafael Loch Batista1, Elaine M. Frade Costa1, Andresa de Santi Rodrigues1,2,
Nathalia Lisboa Gomes1, José Antonio Faria Jr.1, Mirian Y. Nishi1,2,
Ivo Jorge Prado Arnhold1, Sorahia Domenice1,
Berenice Bilharinho de Mendonca1,2

ABSTRACT

Unidade de Endocrinologia do
Desenvolvimento, Laboratório de
Hormônios e Genética Molecular/
LIM42, Hospital das Clínicas,
Disciplina de Endocrinologia,
Faculdade de Medicina da
Universidade de São Paulo
(FMUSP), São Paulo, SP, Brasil
2
Laboratório de Sequenciamento
em Larga Escala (SELA), Faculdade
de Medicina da Universidade de São
Paulo (FMUSP), São Paulo, SP, Brasil
1

Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation
in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame
of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial
(PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants
in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype –
phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated
levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and
social sex of the individual. Open issues in the management of androgen insensitivity syndromes
includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and
genetic counseling. Arch Endocrinol Metab. 2018;62(2):227-35
Keywords
Androgen insensitivity syndrome; androgen receptor; disorders of sex development; 46,XY DSD

Correspondence to:
Berenice Bilharinho de Mendonca
Hospital das Clínicas,
Laboratório de Hormônios
e Genética Molecular
Av. Dr. Enéas de Carvalho Aguiar, 155,
2° andar, Bloco 6
05403-900 – São Paulo, SP, Brasil
beremen@usp.br
Received on Sep/21/2017
Accepted on Jan/18/2018

INTRODUCTION

A

ndrogen Insensitivity Syndrome (AIS) is an
X-linked genetic disease and it is the most
common cause of disorders of sex development (DSD)
in 46,XY individuals (1). The phenotype ranges from
normal female external genitalia in the complete form
(CAIS) to normal male external genitalia associated
with infertility and/or gynecomastia in the mild form
(MAIS). A large spectrum of undervirilized male
external genitalia is observed in the partial form (PAIS)
(2). Mutations in the androgen receptor gene (AR)
are found in most individuals with CAIS but in less
individuals with PAIS (3).
AIS was first described by Morris, in 1953, with the
clinical description of 82 female patients with testes but
female phenotype and for this reason Morris named
the syndrome as testicular feminization (4). Later,
this syndrome was characterized for being a condition
resulting from a complete or partial resistance to
Arch Endocrinol Metab. 2018;62/2

androgens in 46,XY individuals with normal male
gonad development (5).
PAIS should be considered in all individuals with
atypical genitalia at birth regardless of the degree of
external genitalia virilization and MAIS is a possible
diagnosis in males with persistent gynecomastia and or
infertility (6).
Role of Androgens in Male Fetal Development:
androgens are key elements for appropriate internal and
external male sex differentiation. After normal testes
development, the Leydig cells produce testosterone,
which promotes Wolffian duct differentiation into
epididymes, vasa deferentia and seminal vesicles (7). The
conversion of testosterone to dihydrotestosterone by
the 5α-reductase type 2 enzyme promotes male external
genitalia differentiation (8). In humans, the critical period
for genitalia virilization occurs between 8 and 14 weeks of
gestation and depends on the presence of androgens and
of a functioning androgen receptor (9). Impairment of
227

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DOI: 10.20945/2359-3997000000031

Androgen insensitivity syndrome

androgen secretion and defects in the androgen receptor
will compromise the virilization process.

THE HUMAN ANDROGEN RECEPTOR
The AR gene is located at chromosome Xq11-12, is
encoded by eight exons and codifies a 919 aminoacids
protein (Figure 1). The AR is a ligand-dependent
transcription factor composed by three functional
domains as the other nuclear receptors: a large
N-terminal domain (NTD) (residues 1-555), a DNAbinding domain (DBD) (556-623 residues), a hinge
domain (624-665 residues) and a C-terminal ligandbinding domain (LBD) (666–919 residues) (10). The
NTD is encoded by exon 1 and contains a ligandindependent transactivation function 1 (AF1), which
contains two distinct transcription activation units:
Tau-1 (aminoacids 100-370) and Tau-5 (aminoacids
360-485), that are essential for full AR activity. The
DBD is composed by two zinc fingers and connects the
AR to promoter and enhancer regions of AR regulated
genes by direct nuclear DNA binding allowing the
activate functions of NTD and LBD (11). The LBD
is encoded by exons 4-8 and contains 11 α-helices
associated with two anti-parallel β-sheets in a sandwichlike conformation with a central ligand binding pocket,
in which the ligand can bind (12).

CLINICAL PRESENTATION

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CAIS prevalence in 46,XY males is estimated from 1 in
20.400 to 1 in 99.100 (13). Except in cases of familial

inheritance, CAIS is diagnosed in three scenarios: in
fetal life when prenatal sex determination disclosed
a 46,XY karyotype in a fetus with female external
genitalia; in childhood in a girl with inguinal hernia or at
puberty in females with primary amenorrhea (14). The
presence of inguinal hernia in a female child is rare and
could indicate a CAIS diagnosis (13). Patients with AIS
developed breasts with estradiol levels in normal male
range suggesting that the lack of androgen action is the
main driver of breast development in these patients,
rather than an increased estrogen secretion. Menstrual
cycles do not appear since normal production of antimullerian hormone (AMH) by the testis impeded
uterus, cervix and proximal vagina to development. A
shortened blind-ending vagina is observed in almost all
patients and the vaginal measurement varied from 2.5
to 8 cm in CAIS and 1.5 – 4 cm in PAIS. Pubic and
axillary hair are sparse or absent (1,14).
Final height in CAIS is above normal mean female
height, probably due to the action of the growthcontrolling gene (GCY) located at the Y chromosome
(15). Interestingly, newborns with CAIS have the same
size of male newborns, suggesting that postnatal factors
are involved in the final height in these individuals (16).
In our cohort, the final height of CAIS individuals (165.7
± 8.9 cm) was taller than described for Brazilian females,
but lower than expected for Brazilian males (15).
Differential diagnosis of CAIS includes complete
gonadal
dysgenesis,
Mayer-Rokitanski-KusterHauser syndrome and Mullerian ducts anomalies (1).
Biosynthetic enzyme deficiencies are rarely a differential
diagnosis for CAIS (8,17).

Figure 1. A schematic representation of androgen receptor gene and androgen receptor protein.
228

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Androgen insensitivity syndrome

The PAIS clinical phenotype varies according to
the degree of AR residual function and ranges from
proximal hypospadias to micropenis (18). Hypospadias
are a common finding with an estimated prevalence of
1:8000 male births and AR sequencing is necessary to
exclude PAIS diagnosis (19). Gynecomastia observed
at puberty time in patients with atypical genitalia can
be indicative of PAIS (2,20). Differential diagnosis of
PAIS includes all causes resulting in a undervirilized
male external genitalia such as chromosomal defects
(Klinefelter syndrome), genetic diseases (Smith-LemliOpitz syndrome, Denys-Drash syndrome, Frasier
syndrome), partial gonadal dysgenesis, LH receptor
defects, biosynthetic enzyme deficiencies (17,20-lyase
deficiency,
P450
oxidoreductase
deficiency,
17β-hydroxysteroid dehydrogenase deficiency type 3,
5α-reductase 2 deficiency and hypospadias in small for
gestation age boys (8,17).
MAIS is associated with AR mutations but without
external genitalia abnormalities (6). This diagnosis
could be suspected in the investigation of male infertility
or in pubertal gynecomastia (14,18). There are few AR
mutations associated exclusively with MAIS, but this
condition is probably underdiagnosed (3,6).
MAIS can also manifest in a patient with neurological
disorder characterized by bulbar and muscular atrophy
(Kennedy’s disease). This condition is due to the
hyperexpansion of the CAG repeats (> 38), present in
AR exon 1 (21). These patients present with normal
male external genitalia, but testosterone resistance
will develop with disease progression. For MAIS, the
differential diagnosis includes other causes of male
infertility.

ENDOCRINE FEATURES
In AIS the endocrine profile is consistent with androgen
resistance characterized by elevated or normal basal

serum testosterone levels associated with high serum
LH levels (22). Elevated serum AMH and testosterone
levels in a newborn suggest the diagnosis of androgen
insensitivity and also exclude the diagnosis of complete
gonadal dysgenesis (23). In postpuberal patients
estradiol levels are normal or slightly elevated for a male
individual (22). This pattern is seen at mini-puberty or
after puberty. During childhood when gonadotropin
axis is not activated, a hCG stimulation is necessary to
evaluate testosterone secretion by Leydig cells (24). In
MAIS, hormone concentrations are usually normal,
but elevated serum LH and testosterone levels could
be found in these patients (19).
Typically in AIS, basal testosterone and LH levels
are elevated demonstrating the impairment of androgen
negative feedback on the anterior pituitary (22). In
contrast, FSH levels are usually normal in AIS. This is
explained by the fact that FSH is mainly regulated by
gonadal inhibin (25). Although there are differences in
the AR residual function among the mutated receptors
between CAIS and PAIS phenotypes, no difference
are observed in hormonal levels (20,22). Serum LH,
FSH estradiol, DHT were not different in subjects with
CAIS and PAIS (Table 1).

MOLECULAR DEFECTS IN THE ANDROGEN
RECEPTOR GENE
The AIS diagnosis is confirmed by the presence of
allelic variants in the AR gene (1,26). About 30% of
AR mutations in AIS are de novo and sequencing of
the entire AR gene is recommended for all 46,XY DSD
newborns, regardless of a familial history of DSD or AIS
(26). In the absence of allelic variants in AR a multiplex
ligation-dependent probe amplification (MLPA) can
be helpful in order to detect deletions, insertions and
duplications in the AR gene (26). There are more than
1000 AR mutations described in a website database

Table 1. Basal hormone levels in patients with AIS
Phenotype

LH
(U/L)

FSH
(U/L)

Testosterone
ng/dL

Estradiol
pg/mL

CAIS
n = 11

14 – 43*
26**

3.5 – 16*
7.4**

186 – 1033*
342**

10 – 40*
27**

(22)

PAIS
n = 14

9 – 32*
26**

– 34*
5.0**

157 – 1592*
1032

20 – 109*
49

(22)

CAIS
n = 42

5.5 – 51
18.5

0.4 – 16**
3.5*

173 – 1497*
576**

4.8 – 70*
30.7**

(60)

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Reference

* Range; ** Median.
Arch Endocrinol Metab. 2018;62/2

229

Androgen insensitivity syndrome

associated with AIS and prostate cancer (http://www.
mcgill.ca/androgendb) and around 600 of them were
described in AIS (3). Mutations are found along the
AR gene, being more frequent in exon 1 (the largest
AR exon, which encodes the NTD). Defects in the
NTD domain are more frequent in CAIS’s patients
and variants in exons 5 and 6 (that encode LBD) are
more frequent in PAIS’s patients (3). Almost all AR
mutations in MAIS were found in the NTD, but
there is a low number of AR mutations related to this
phenotype.
The most common AR allelic variants in all AIS
phenotypes are non-synonymous point mutations.
Insertions and deletions causing a frameshift leading
to a premature stop codon downstream are more
frequently reported in CAIS’s patients. Allelic variants
affecting mRNA splicing are reported in CAIS and
PAIS phenotypes. Rarely, synonymous allelic variants
affecting splicing sites has been described in PAIS (27)
and in CAIS individuals (28).
Large structural mutations (exon 1 deletion, exon 2
duplication, exon 3 deletion, exon 4-8 (LBD domain)
deletion and deletion of entire AR gene) have been
described but are very rare in AIS (3). Interesting,
a deletion of an entire exon (exon 4) was previously
described in a phenotypic male with azoospermia (29).
Postzygotic AR allelic variants resulting in somatic
mosaicism are rarely described in AIS (30). In this
situation the variant appears in heterozygote instead of
hemizygote state. AR allelic variants in heterozygosis
was also identified in some individuals with 47,XXY
karyotype causing AIS (31).
There is not a perfect correlation between genotype
and phenotype in AIS. In the AR mutation database,
there are some AR allelic variants that can cause
different phenotypes (Table 2). The explanation for
this is not completely understood. It is hypothesized
that AR co-regulators (activators and repressors) are
implicated with this phenomenon. Other possibilities
are variations in the level of 5α-reductase type 2 activity
resulting in different DHT availability, and the presence

of germ-line AR allelic variants at a post zygote stage
conferring somatic mosaicism (31).

CLINICAL MANAGEMENT OF AIS
AIS patients have complex issues including functional,
sexual and psychosocial aspects. Sex assignment,
external genitalia adequacy for social sex, hormonal
replacement, psychosexual outcome, ideal time for
gonadectomy, infertility and genetic counseling are
issues that need attention in AIS care. All of them
demand flexible, sensible and individualized procedures
to achieve good results.

CLINICAL MANAGEMENT OF CAIS
After diagnosis, the first aspect to be considered is the
time for bilateral gonadectomy. In a girl, maintenance of
the gonads will allow spontaneous breast development,
though breast development is similar with estrogen
replacement in gonadectomized females. So far,
gonadectomy is performed at early age, in order to avoid
the risk of malignancies and the psychosocial difficulties
in submitting an adolescent female to gonadectomy
(24). When gonadectomy is performed before puberty,
estrogen replacement is necessary to induce puberty.
In general, hormonal replacement is started at the
age of 11-12 years with oral or transdermal estrogen.
Both ways are adequate and the patient and family
can choose the route in which the compliance will be
better (18). Due to the absence of uterus, progesterone
replacement is not necessary.
Genitoplasty is not necessary in CAIS and vaginal
dilation promotes an adequate vaginal length vaginal
dilation should occur after puberty or when the
patient refers to desire to initiate sexual activity (32).
Most of the individuals (80%) who were submitted to
vaginal dilation referred satisfactory and some of them
reported dyspareunia (33). There are many vaginoplasty
techniques (34), but non-surgical dilation is effective,
safe, non expensive and normalizes vaginal length and

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Table 2. AR allelic variants identified in more than one AIS phenotype (3)
Allelic variants

Phenotype

p.Leu174, p.Arg616Pro, p.Asn693del, p.Asn706Ser,p.Gly744Val, p.Met746Phe, p.Met750Val, p.Trp752*, p.Ala766Thr, p.Pro767Ser,
p.Arg775His, p.Arg841His, p.Ile843Thr, p.Val867Met, p.Val890Met, p.Ser704Gly

CAIS, PAIS

p.Pro392Ser, p.Leu548Phe, p.Arg616His, p.Asp696Asn, p.Met781Ile, p.Arg856His, p.Ala646Asp

CAIS, PAIS, MAIS

p.Tyr572His, p.Arg608Gly, p.Asn757Ser, p.Arg789Ser, p.Gln799Glu, p.Thr801Ile, p.Ser815Asn, p.Leu822Val, p.Ala871Gly, p.Gly216Arg,
p.Arg608Gly
230

PAIS, MAIS

Arch Endocrinol Metab. 2018;62/2

Androgen insensitivity syndrome

sex intercourse (32). Because of that, surgical creation
of a vagina should be avoid regardless of the surgical
technique (32).

repeats in the AR exon 1 and a number of patients also
have testicular atrophy, gynecomastia, oligospermia
and erectile dysfunction (37).

CLINICAL MANAGEMENT OF PAIS

HORMONAL REPLACEMENT IN AIS

PAIS diagnosis is usually suspected in a newborn with
atypical genitalia and palpable gonads. Most of the
patients are raised as male. The degree of external
genitalia virilization is related to the residual AR
function and can be predictive of androgen response at
puberty. In male patients, correction of cryptorchidism
and hypospadias are recommended as soon as possible,
preferably before two years of age (35).
PAIS males frequently develop gynecomastia at
puberty and surgical correction is generally necessary
(22). High testosterone or DHT trials (intramuscular
or topic testosterone esters or topic DHT) can be
use to increase penile length and to improve other
virilization signs (18,30). The results are unpredictable
but are usually limited. Maximum virilization effect
is observed after 6 months of high androgen usage
treatment, subsequently, androgen therapy can be
withdrawn in the patients with normal testes and
preserved testosterone secretion.
For individuals raised as females, bilateral
gonadectomy is recommended in childhood to avoid
virilization and to eliminate the risk of testicular tumors
(36). Genitoplasty is usually necessary in PAIS females
and estrogen replacement is mandatory at pubertal
time, with similar recommendation as describe for
CAIS patients (15).
For MAIS, there is little information about
clinical outcomes. Gynecomastia and infertility are
the usual clinical presentation of this phenotype (6)
and mastectomy is recommended for gynecomastia
correction. This phenotype is observed in individuals
with Kennedy’s disease, which is more commonly
known as spinal and bulbar muscular atrophy (SBMA).
This syndrome is caused by an excessive number of CAG

Hormonal replacement is mandatory for all
gonadectomized individuals. In females, the purpose
is the development of secondary sexual characteristics
and an adequate and bone mass (2). Estrogen can be
introduced in low doses (one quarter of the adult dose),
at 9 – 11 years of age, with titration of this dosage every
6 months (20). The time for complete feminization
is expected to be about 2 years. Oral or transdermic
estrogen are alternative ways for estrogen replacement.
The initial dose is 0.25 mg/day of 17β-estradiol
increasing the dose each 6 months considering the
progression of breast development. After complete
breast development, a regular dose can be introduced
(1-2 mg/day of 17β-estradiol continuously) (9).
In male individuals, the testes are able to produce
testosterone. In male AIS, at pubertal age, high
testosterone doses (200–500 mg twice a week) can be
used, in order to increase the penile size and to promote
virilization (1). Maximum penile length is obtained
after six months of treatment with high testosterone
doses. After this period, the dose of testosterone when
necessary should return to the maintenance dose. The
use of DHT in male PAIS has been tested (0.3 mg/kg
of androstanolone gel 2.5% for 4 months) and mixed
results were obtained following DHT therapy (38).

Type of defect

CAIS

PAIS

MAIS

Non-synonymous

155

125

41

Stop codon

57

2

0

Indel

41

4

2

Duplication

6

0

0

Total

259

131

43

Arch Endocrinol Metab. 2018;62/2

Disorders of sex development are recognized as a risk
factor for type II germ cell tumors (GCTs). These tumors
are classified as seminomatous and non-seminomatous
types (39). The seminomatous tumors referred to
seminoma (testis) and to dysgerminoma (ovary and
dysgenetic gonads). In the non-seminomatous group,
many differentiated variants can be identified according
to the cellular origin, being the teratomas from somatic
differentiation, yolk sac tumor and choriocarcinoma
from extra-embryonic differentiation, and embryonal
carcinoma from stem cells (27). These tumors derivate
from a non-invasive precursor named carcinoma
in situ – CIS – or Intrabular germ cell neoplasia
unclassified – IGCNU). In 2016, the World Health
Organization suggested to change the nomenclature of
231

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Table 3. Types of androgen receptor allelic variants related to AIS reported
in the androgen receptor mutations database

GONADAL TUMOR RISK IN AIS

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Androgen insensitivity syndrome

this initial germinative neoplastic lesion from CIS or
IGCNU to germ cell neoplasia in situ (GCNIS) (40).
GCNIS are always non-invasive, but 50% of GCNIS
progress to invasive GCTs within 5 years. The risk
of GCTs development is related to the presence of a
Y chromosome, but is not the same for the different
etiologies of 46,XY DSD. So far, some factors, as
chronological age and gonadal location can influence
GCTs development (41).
In CAIS, the risk of GCTs is considered low and
related to age (36). The estimated risk of gonadal tumors
in CAIS gonads was about 0.8% - 22% (42). However,
most old series included patients without confirmed AR
mutation or without description of age at gonadectomy.
The reports of malignant GCTs before puberty in CAIS
are very rare (43). There is only one documented report
of an invasive yolk-sac tumor in a CAIS individual
before puberty. This occurred in a 17-months-old
CAIS girl with abdominal gonads (44). After puberty,
the risk is low, but not negligible. In a study, including
133 patients with CAIS, the gonads’ histological and
immunohistochemical findings showed a prevalence of
1.5% (2/133) for malignancies (45). The low incidence
of GCTs in CAIS individuals can be explain by the rapid
decline of germ cells after the first year of life (46).
PAIS individuals may maintain their germ cells
because of the presence of residual androgen receptor
responsiveness, differently of CAIS (46). Therefore, the
incidence of GCTs in PAIS (15%) is higher than in CAIS
(42). In cases of PAIS with untreated undescended testes
the GCTs risk may be as high as 50% (47). Therefore,
laparoscopic bilateral gonadectomy is indicated in all
PAIS females and orquidopexy in scrotum in the male
patients (48).
In patients who maintained the gonads, a careful
monitoring including ultrasonography (US) or MRI
has been suggested (43). Due to easy access and low
cost, US remain the first choice for monitoring retained
gonads. MRI has demonstrated adequate sensitivity to
detect benign gonadal lesions, such as cysts or Sertoli
cell adenomas, but failed to detect GCNIS (49). Annual
US follow-up of labioscrotal and/or inguinal gonads
is recommended. For abdominal gonads monitoring
MRI is more helpful (50).

FERTILITY IN AIS
A normal androgen receptor is necessary for normal
male reproduction, because testosterone and FSH, are
232

essential factors for male spermatogenesis. Therefore,
mutations in the androgen receptor gene have been
searched in order to identify possible causes for male
infertility. As previously described, infertility may be the
only clinical manifestation of undervirilization in MAIS
phenotype (6,51).
The strategy to obtain fertility in AIS individuals has
not been defined yet (52). In CAIS, there is absence
of uterus and testes histology reveals incomplete
spermatogenesis, increased fibrosis, Leydig cell
hyperplasia and low frequency of spermatogonia
conferring a very low potential to fertility. In addition,
the viability of male germ cells in CAIS is restricted to
the first two years of life and for fertility in adult life germ
cells should be preserved before this age (46). In PAIS
individuals, some residual androgen receptor function is
preserved, but not usually enough to promote fertility
(46). Indeed, infertility is the rule in AIS (22).
Probably, fertility is the most sensitive outcome
which depends of an intact androgen receptor. For it,
MAIS individuals can present only infertility (6,51).
However, the p.G824K and p.R840C AR variant
allelics, were found in male individuals with preserved
fertility (51,53).
A successful fertility was recently described in a
PAIS individual harboring the p.V686A AR variant,
after prolonged high-dose testosterone therapy
(250 mg of testosterone enanthate weekly by four
years) causing improvement in sperm count. The
gonadotropin concentrations remained unaffected and
intracytoplasmic sperm injection with a single sperm
directly into an egg resulted in proved fertility (54).
In general, infertility in AIS is the rule. The evidence
of sperm count improvement after high doses of
testosterone (as described above) can be an indicative
of fertility success, but should be tested in further
studies as well as the use of aromatase inhibitors and
clomiphene citrate to obtain fertility in these patients

PSYCHOLOGICAL OUTCOMES
Psychological support is essential for AIS individuals
and their parents, in general (55). Dialogue about
fertility, sexuality and karyotype are delicated issues to
be approached with AIS individuals.
The gender identity, gender role and sexual
orientation show a female pattern in CAIS individuals.
In PAIS patients, in general, gender identity aligned
with both sex of rearing male or female (56).
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Androgen insensitivity syndrome

CONCLUSION
AIS is the most common molecular diagnosis in
newborns with 46,XY DSD and results of an AR
defect. It has an X-linked inheritance and affects 50%
of the male offspring. In CAIS, the diagnosis can be
done intrauterus, at birth, childhood or after puberty.
In PAIS, the diagnosis is usually at birth due to the
atypical external genitalia. In MAIS, the diagnosis
should be considered in cases of pubertal gynecomastia
and male infertility. AR defects are found along AR
gene in all AIS phenotypes. Non-synonymous point
mutations are the commonest AR defects reported
in AIS. Molecular diagnosis is achieved in almost all
patients with CAIS and in a lower frequency in PAIS
individuals. AIS is characterized by elevated serum
LH and testosterone. In CAIS, there is a low risk of
GCTs before puberty and postponing surgery to after
puberty may allow the development of spontaneous
puberty. In PAIS there is a risk of GCTs in 15% of the
patients, and bilateral gonadectomy is recommended at
childhood in all individuals raised in the female social
sex. For males with PAIS, the testis should be placed
in the scrotum and regularly monitored. Fertility was
described in one PAIS individuals, and therapeutic
strategy for successful fertility could be experienced in
PAIS and MAIS individuals. In AIS, gender identity
usually follows the sex of rearing, but quality of sexual
life, sexual functioning and quality of life can be slightly
compromised and are important issues for keeping
patients in psychological care.
Funding: this work was supported by: Fundação de Amparo à
Pesquisa do Estado de São Paulo Grant 2013/02162-8, Núcleo
Arch Endocrinol Metab. 2018;62/2

de Estudos e Terapia Celular e Molecular (NETCEM) and Conselho Nacional de Desenvolvimento Científico e Tecnológico Grant
303002/2016-6 (to B.B.M.); Fundação de Amparo à Pesquisa do
Estado de São Paulo 2014/50137-5 (to SELA).
Disclosure: no potential conflict of interest relevant to this article
was reported.

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233

Copyright© AE&M all rights reserved.

Gender change is very rarely described in CAIS and
there are just four cases of gender change in individuals
with CAIS (57). Therefore, gender dysphoria in CAIS
is considered truly transgenderism. However, sexual
functioning and sexual quality of life demonstrated lesspositive outcome in CAIS patients in comparison with
normal woman (58).
Although there is no inconsistency in gender identity,
male PAIS individuals show disappointment with
undervirilization signs. The absence or paucity of facial
and body hair, the high-pitched voice compromised
their self-perception of manhood (59). In female
individuals, low scores in feminility scales have been
reported (58). An impairment of sexual functioning is
reported in male and female PAIS individuals (58).

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39. Wünsch L, Holterhus PM, Wessel L, Hiort O. Patients with
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molecular diagnosis. BJU Int. 2012;110(11 Pt C):E958-65.

24. Ahmed SF, Cheng A, Hughes IA. Assessment of the gonadotrophingonadal axis in androgen insensitivity syndrome. Arch Dis Child.
1999;80(4):324-9.

40. Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The
2016 WHO Classification of Tumours of the Urinary System and
Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.
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25. Lahlou N, Bouvattier C, Linglart A, Rodrigue D, Teinturier C. [The
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development. Endocr Dev. 2014;27:172-84.

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Disorders of sex development: effect of molecular diagnostics.
Nat Rev Endocrinol. 2015;11(8):478-88.

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(DSD). Best Pract Res Clin Endocrinol Metab. 2007;21(3):480-95.

27. Hellwinkel OJ, Holterhus PM, Struve D, Marschke C, Homburg
N, Hiort O. A unique exonic splicing mutation in the human
androgen receptor gene indicates a physiologic relevance of
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43. Döhnert U, Wünsch L, Hiort O. Gonadectomy in Complete
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34. Hayashida SA, Soares JM Jr, Costa EM, da Fonseca AM,
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235

Orphanet Journal of Rare Diseases
BioMed Central

Open Access

Review

Oculocutaneous albinism
Karen Grønskov, Jakob Ek and Karen Brondum-Nielsen*
Address: Kennedy Center. National Research Center for Genetics, visual Impairment and Mental Retardation, Gl. Landevej 7, 2600 Glostrup,
Denmark
Email: Karen Grønskov - kag@kennedy.dk; Jakob Ek - jek@kennedy.dk; Karen Brondum-Nielsen* - kbn@kennedy.dk
* Corresponding author

Published: 2 November 2007
Orphanet Journal of Rare Diseases 2007, 2:43

doi:10.1186/1750-1172-2-43

Received: 10 May 2007
Accepted: 2 November 2007

This article is available from: http://www.OJRD.com/content/2/1/43
© 2007 Grønskov et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Oculocutaneous albinism (OCA) is a group of inherited disorders of melanin biosynthesis
characterized by a generalized reduction in pigmentation of hair, skin and eyes. The prevalence of
all forms of albinism varies considerably worldwide and has been estimated at approximately 1/
17,000, suggesting that about 1 in 70 people carry a gene for OCA. The clinical spectrum of OCA
ranges, with OCA1A being the most severe type with a complete lack of melanin production
throughout life, while the milder forms OCA1B, OCA2, OCA3 and OCA4 show some pigment
accumulation over time. Clinical manifestations include various degrees of congenital nystagmus,
iris hypopigmentation and translucency, reduced pigmentation of the retinal pigment epithelium,
foveal hypoplasia, reduced visual acuity usually (20/60 to 20/400) and refractive errors, color vision
impairment and prominent photophobia. Misrouting of the optic nerves is a characteristic finding,
resulting in strabismus and reduced stereoscopic vision. The degree of skin and hair
hypopigmentation varies with the type of OCA. The incidence of skin cancer may be increased. All
four types of OCA are inherited as autosomal recessive disorders. At least four genes are
responsible for the different types of the disease (TYR, OCA2, TYRP1 and MATP). Diagnosis is based
on clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular
symptoms. Due to the clinical overlap between the OCA forms, molecular diagnosis is necessary
to establish the gene defect and OCA subtype. Molecular genetic testing of TYR and OCA2 is
available on a clinical basis, while, at present, analysis of TYRP1 and MATP is on research basis only.
Differential diagnosis includes ocular albinism, Hermansky-Pudlak syndrome, Chediak-Higashi
syndrome, Griscelli syndrome, and Waardenburg syndrome type II. Carrier detection and prenatal
diagnosis are possible when the disease causing mutations have been identified in the family. Glasses
(possibly bifocals) and dark glasses or photocromic lenses may offer sufficient help for reduced
visual activity and photophobia. Correction of strabismus and nystagmus is necessary and
sunscreens are recommended. Regular skin checks for early detection of skin cancer should be
offered. Persons with OCA have normal lifespan, development, intelligence and fertility.

Disease name

Definition

Oculocutaneous albinism

Oculocutaneous albinism (OCA) is a group of four autosomal recessive disorders caused by either a complete lack
or a reduction of melanin biosynthesis in the melanocytes

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resulting in hypopigmentation of the hair, skin and eyes.
Reduction of melanin in the eyes results in reduced visual
acuity caused by foveal hypoplasia and misrouting of the
optic nerve fibres. The clinical spectrum of OCA varies,
with OCA1A being the most severe type characterized by
a complete lack of melanin production throughout life,
while the milder forms OCA1B, OCA2, OCA3 and OCA4
show some pigment accumulation over time. The different types of OCA are caused by mutations in different
genes but the clinical phenotype is not always distinguishable, making molecular diagnosis a useful tool and essential for genetic counseling.

Epidemiology
Albinism can affect people of all ethnic backgrounds and
has been extensively studied. Approximately one in
17,000 people have one of the types of albinism [1]. This
suggests that about 1 in 70 people carry a gene for OCA.
Prevalence of the different forms of albinism varies considerably worldwide, partly explained by the different
founder mutations in different genes and the fact that it
can be difficult clinically to distinguish between the different subtypes of albinism among the large normal spectrum of pigmentation. OCA2 is the most prevalent form
worldwide [2] (Table 1).
• OCA1 has a prevalence of approximately 1 per 40,000
[3] in most populations but is very uncommon among
African-Americans.
• In contrast, OCA2 is the most common type of albinism
in African Black OCA patients. The overall prevalence of
OCA2 is estimated to be 1:36,000 in the USA, but is about
1:10,000 among African Americans [4]. It affects 1 in
3,900 of the population in some parts of the southern part
of Africa [5].
• OCA3 or Rufous oculocutaneous albinism has been
reported to affect 1:8,500 individuals in Africa, whereas it
is very rare in Caucasians and Asiatic populations [6].

• Recently, mutations in a fourth gene were shown to be
the cause of albinism, OCA4, [7] and were reported to
explain the disease in approximately 5–8% of German
patients with albinism [8] but 18% of Japanese patients
[9].

Clinical description
All types of OCA and ocular albinism (OA) have similar
ocular findings, including various degrees of congenital
nystagmus, hypopigmentation of iris leading to iris translucency, reduced pigmentation of the retinal pigment epithelium, foveal hypoplasia, reduced visual acuity usually
in the range 20/60 to 20/400 and refractive errors, and
sometimes a degree of color vision impairment [1,10]
(Figure 1). Photophobia may be prominent. Iris translucency is demonstrable by slit lamp examination. A characteristic finding is misrouting of the optic nerves,
consisting in an excessive crossing of the fibres in the optic
chiasma, which can result in strabismus and reduced stereoscopic vision [11]. The abnormal crossing of fibres can
be demonstrated by monocular visual evoked potential
[12]. Absence of misrouting excludes the diagnosis of
albinism.
The degree of skin and hair hypopigmentation varies with
the type of albinism but is in general reduced [10] (Table
1).
• In OCA1A the hair, eyelashes and eyebrows are white,
and the skin is white and does not tan. Irises are light blue
to almost pink, and fully translucent (Figure 2). Pigment
does not develop and amelanotic nevi may be present.
The symptoms do not vary with age or race. Visual acuity
is 1/10 or less, and photophobia is intense.
• In OCA1B, the hair and skin may develop some pigment
with time (after 1 to 3 years), and blue irises may change
to green/brown. Temperature-sensitive variants manifest
as having depigmented body hairs, and pigmented hairs
on hands and feet due to lower temperatures. Visual acu-

Table 1: The four known types of OCA

Gene

Gene product

Chr. localization

Size

TYR

Tyrosinase (TYR)

11q14.3

65 kb (529aa)

OCA2
(p gene)
TYRP1

OCA2

15q11.2-q12

OCA1
OCA1A
OCA1B (Yellow alb.)
345 kb (838aa) OCA2 (Brown OCA in Africans)

Tyrosinase-related
protein 1 (TYRP1)
Membrane-associated
transporter protein
(MATP)

9p23

17 kb (536aa)

OCA3 (Rufous OCA)

5p13.3

40 kb (530aa)

OCA4

MATP

Disease name

Prevalence
1:40,000

1:36,000 (white Europeans)
1:3,900–10.000 (Africans)
Rare (white Europeans, Asians)
1:8,500 (Africans)
Rare (white Europeans) 1:85,000
(Japanese)

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Orphanet Journal of Rare Diseases 2007, 2:43

Figure
Fundus
ture
of apicture
1normalofeye
a patient
(b) with albinism (a) and fundus picFundus picture of a patient with albinism (a) and fundus picture of a normal eye (b).

ity is 2/10. This phenotype was previously known as yellow albinism.
• In OCA2, the amount of cutaneous pigment may vary,
and newborn nearly always have pigmented hair. Nevi
and ephelids are common. Iris color varies and the pink
eyes seen in OCA1A are usually absent. Visual acuity is
usually better than in OCA1, and can reach 3/10. In Africans, brown OCA is associated with light brown hair and
skin, and gray irises. Visual acuity may reach 3/10.
• OCA3 results in Rufous or red OCA in African individuals, who have red hair and reddish brown skin (xanthism). Visual anomalies are not always detectable,
maybe because the hypopigmentation is not sufficient to
alter the development.
• OCA4 cannot be distinguished from OCA2 on clinical
findings.

http://www.OJRD.com/content/2/1/43

11q14.3 [13]. The gene consists of 5 exons spanning
about 65 kb of genomic DNA and encoding a protein of
529 amino acids [14]. TYR (EC 1.14.18.1) is a copper-containing enzyme catalysing the first two steps in the melanin biosynthesis pathway, converting tyrosine to Ldihydroxy-phenylalanine (DOPA) and subsequently to
DOPAquinone [15]. Mutations completely abolishing
tyrosinase activity result in OCA1A, while mutations rendering some enzyme activity result in OCA1B allowing
some accumulation of melanin pigment over time.
Almost 200 mutations in TYR are known [16]. As with all
recessive disorders, the "mildest" mutation is determining
for the phenotype. It has been shown that mutations in
the mouse Tyr gene cause the Tyr protein to be retained in
the endoplasmic reticulum, with subsequently early degradation [17] (Figure 3).
• Mutations in the OCA2 gene (formerly known as the Pgene) (MIM 203200) cause the OCA2 phenotype (MIM
203200) [18]. The gene consists of 24 exons (23 coding),
spanning almost 345 kb of genomic DNA in the region
15q11.2-q12, and encoding a protein of 838 amino acids
[19]. The OCA2 protein is a 110 kDa integral melanosomal protein with 12 predicted transmembrane domains
[18,20]. OCA2 protein is important for normal biogenesis
of melanosomes [21,22], and for normal processing and
transport of melanosomal proteins such as TYR and
TYRP1 [23-26] (Figure 3). TYR stably expressed in a
human cell line is retained in perinuclear compartments;
this mislocalization can be reverted if OCA2 is coexpressed [27]. It seems that OCA2 exerts at least some of
its effects by maintaining an acidic pH in melanosomes
[27]. In the Human Gene Mutation Database (HGMD)
[16], 72 mutations in OCA2 are listed to cause OCA.

Etiology
OCA is a group of congenital heterogeneous disorders of
melanin biosynthesis in the melanocytes (Figure 3). At
least four genes are responsible for the different types of
OCA (OCA1-4) (Table 1). Most patients are compound
heterozygotes, i.e. harbouring two different mutations in
one of the genes.
• OCA1 (MIM 203100) is caused by mutations in the
tyrosinase gene (TYR, MIM 606933) on chromosome

• OCA3 (MIM 203290) is caused by mutations in tyrosinase-related protein 1 (TYRP1, MIM 115501, 9p23) [28].
TYRP1 spans almost 17 kb genomic DNA, and consists of
8 exons encoding a protein of 536 amino acids [29].
TYRP1 is an enzyme in the melanin biosynthesis pathway,
catalysing the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) monomers into melanin (Figure 3).
Studies of mouse melanocytes showed that Tyrp1 functions to stabilize Tyr, and that mutations in Tyrp1 cause a

Figure
Eyes
from
2 a patient with OCA1A
Eyes from a patient with OCA1A. Note that the irises are almost pink, and fully translucent.

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Figure
cyte
Tyrosinase
and3in (TYR)
the melanosome,
and Tyrosinase-related
respectively protein 1 (TYRP1) processing and the melanin biosynthetic pathway in the melanoTyrosinase (TYR) and Tyrosinase-related protein 1 (TYRP1) processing and the melanin biosynthetic pathway in the melanocyte and in the melanosome, respectively. A) Schematic representation of melanosome biogenesis in the melanocyte and trafficking of TYR and TYRP1 from the endoplasmatic reticulum (ER) via Golgi apparatus to the developing melanosome. Places
are indicated where the transport or sorting of TYR and TYRP1 from the synthesis in the ER to the melanosomes is abolished
caused by mutations in the four genes found to be responsible for OCA (OCA1 to OCA4, respectively) (adapted from [49]).
B) Illustration of the melanin (eumelanin/pheomelanin) biosynthesis pathway in the melanosome. DHI: 5,6-Dihydroxyindole,
DHICA: 5,6-Dihydroxyindole-2-carboxylic acid, TYR: tyrosinase, TYRP1: Tyrosinase-related protein 1 (DHICA oxidase), DCT:
Dopachrome tautomerase.
delayed maturation and an early degradation of Tyr [17]
(Figure 3). Until recently, OCA3 was only known in individuals of African descent, however currently mutations in
TYRP1 have been identified in both a large Pakistani family [30] and in a Caucasian patient [6].
• Mutations in the membrane-associated transporter protein gene (MATP, also known as SLC45A2, MIM 606202)
cause OCA4 (MIM 606574) [7]. MATP consists of 7 exons
spanning approximately 40 kb of genomic DNA, mapping
to chromosomal position 5p13.3. The MATP protein of
530 amino acids contains 12 putative transmembrane
domains and shows sequence and structural similarity to
plant sucrose transporters; it is expressed in melanosomal
cell lines [31,32]. The function of MATP is still unknown,

but studies from Medaka fish show that the MATP protein
plays an important role in pigmentation and probably
functions as a membrane transporter in melanosomes
[31] (Figure 3). Mutations in MATP were found for the
first time in a Turkish OCA patient [7], and have since
been found in German, Japanese and Korean OCA
patients [8,9,33,34].

Diagnostic methods
The diagnosis of OCA is based on clinical findings of
hypopigmentation of the skin and hair, in addition to the
characteristic ocular symptoms (Figure 1). However, due
to the clinical overlap between the OCA subtypes, molecular diagnosis is necessary in order to establish the gene
defect and thus the OCA subtype. Molecular genetic test-

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Orphanet Journal of Rare Diseases 2007, 2:43

ing of TYR and OCA2 are available on a clinical basis,
while at present, analysis of TYRP1 and MATP is on
research basis only. Molecular genetic testing is based on
mutational analysis of the genes, by standard screening
methods such as denaturing high performance liquid
chromatography (DHPLC) or single stranded conformational polymorphism (SSCP), followed by DNA sequencing.

http://www.OJRD.com/content/2/1/43

Previously, prenatal diagnosis has been performed on
skin biopsies from the fetus [36,37]. Requests for prenatal
diagnosis for OCA are not common, and may reflect the
nature of the condition (not affecting intellectual functions or general health). However, many centers including
ours would consider prenatal testing after careful genetic
counseling of the parents.

Management
Mutational analysis of TYR is complicated by the presence
of a pseudogene harbouring sequences highly similar to
exon 4 and 5 of TYR. This can be overcome either by digestion of pseudogene sequences with restriction enzymes
prior to PCR amplification or by use of specific primers
only amplifying TYR sequences [35].
Due to the presence of numerous polymorphisms, mutational analysis of OCA2 is difficult and until a functional
assay is available, investigation of control chromosomes
in addition to in silico analyses of amino acid substitutions
are necessary in order to substantiate the probable deleterious effect of a (missense) mutation.

Genetic counseling and antenatal diagnosis
All four types of OCA are inherited as autosomal recessive
disorders. Thus, the parents of an affected child are obligate carriers, the recurrence risk for another affected child
is 25%, and healthy sibs are at 67% risk of being carriers.
Offspring of an affected person are obligate carriers. Carriers are asymptomatic.
In most cases, there is no previous family history of albinism but the condition does occur in individuals of two
generations of a family, so called pseudodominance, and
is due to an affected person having children with a person
who is a carrier.
In African populations, there is a high frequency of OCA2
mutant alleles, hence affected patients in several generations may be seen.
Carrier detection and prenatal diagnosis are possible
when the disease causing mutations have been identified
in the family. Both disease causing mutations in an
affected person have to be identified and established to be
on the paternal and maternal chromosome, respectively,
before prenatal diagnosis can be performed in pregnancies at 25% risk for an affected child. The testing can be
done on DNA extracted from chorion villus sampling
(CVS) at 10–12 weeks gestation or on DNA extracted from
cultured amniocytes. Preimplantation diagnosis using
molecular genetic analysis is also possible in principle,
but to our knowledge, this has not been carried out.

Management of eye problems
Reduced visual acuity can be helped in various ways. Clinics specialized in low vision will provide the expertise.
Glasses, possibly bifocals, may often be of sufficient help.
Photophobia can be helped with dark glasses or
photocromic lenses that darken with exposure to bright
light. Nystagmus may be helped with contact lenses or
surgery of the eye muscles. Certain positions of the head
may dampen nystagmus. For strabismus it may be necessary to patch one eye in children to force the non-preferred eye to be used.

Children should be given special attention at school, for
instance with high contrast written material, large type
textbooks, various optic devices as enlargement machines
(closed circuit TV), and the use of computers.
Skin
Most people with severe forms of OCA do not tan and easily get sunburned. Those forms with a little pigment developing with age may not be very bothered by the sun.
Sunscreens are recommended with at least a sun protection factor of 15. Ultraviolet rays can penetrate light Tshirts especially when wet. Now, T-shirts have been developed which protect against the sun even when wet. The
incidence of skin cancer is increased in patients with OCA
[3]. Since the prevalence of OCA2 is high in Africa, this
may pose a serious health problem.

Differential diagnosis
It has become evident that heterogeneity exists within
oculocutaneous albinism, and several disorders with characteristic of OCA in addition to other symptoms have
been identified. On the contrary, in Ocular Albinism
(OA) the hypopigmentation is limited to the eyes resulting in irides that are blue to brown, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic
fibres and reduced visual acuity [38]. The gene OA1 is
localized on the X chromosome and only fibersboys are
affected [39]. In young boys with light complexion, of e.g.
Scandinavian extraction, some difficulty in the differential
diagnosis of OCA versus OA is not uncommon.
Among disorders where albinism is part of a larger syndrome are Hermansky-Pudlak syndrome (HPS), ChediakHigashi syndrome (CHS), Griscelli Syndrome, and

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Orphanet Journal of Rare Diseases 2007, 2:43

Waardenburg Syndrome type II (WS2). All, except WS2,
are inherited as autosomal recessive traits and can be distinguished on the basis of clinical and biochemical criteria. Several subtypes exist within the different diagnoses.
Further, an association of hypopigmentation in Prader
Willi syndrome and Angelman disease with a deletion on
15q11 has been found, presumable caused by mutations
in OCA2 [40].
• The Hermansky-Pudlak syndrome is characterized by
hypopigmentation and the accumulation of a material
called ceroid in tissues throughout the body [41]. Further,
patients exhibit severe immunologic deficiency with neutropenia and lack of killer cells [42]. HPS is very rare,
except in Puerto Rico where it affects approximately 1 in
1,800 individuals [43]. The most important medical problems in HPS are related to interstitial lung fibrosis, granulomatous colitis and mild bleeding problems due to a
deficiency of granules in the platelets [44].

http://www.OJRD.com/content/2/1/43

genomic deletions or single exon deletions not identified
by traditional screening methods may explain the disease
in a fraction of the patients. In addition, a percentage of
genetically unresolved cases might be explained by mutations in not yet identified OCA genes. Finally, the biological function of the gene products of the genes identified
as the cause of albinism is not clarified and further elucidation of these mechanisms may give clues to further candidate genes where mutations are the cause of new
subtypes of OCA.

Abbreviations
CHS : Chediak-Higashi syndrome
CVS : Chorion villus biopsy
DOPA : L-dihydroxy-phenylalanine
HPS : Hermansky-Pudlak syndrome

• The Chediak-Higashi syndrome is a rare condition that
includes an increased susceptibility to bacterial infections,
hypopigmentation, prolonged bleeding time, easy bruisability, and peripheral neuropathy. The skin, hair, and eye
pigment is reduced or diluted in CHS [45,46].

OA : Ocular albinism

• The Griscelli syndrome is a rare disorder with immune
impairment or neurological deficit and hypopigmentation of skin and hair, and the presence of large clumps of
pigment in hair shafts [47].

Competing interests

OCA : Oculocutaneous albinism
WS2 : Waardenburg Syndrome type II

The author(s) declare that they have no competing interests.

Authors' contributions
• A syndrome of sensory deafness and partial albinism is
referred to as the albinism-deafness syndrome or the
Waardenburg syndrome [48].

All authors contributed to a draft of the manuscript and
were subsequently involved in revising the manuscript
critically for important intellectual content. All authors
read and approved the final manuscript.

Prognosis
Lifespan in patients with OCA is not limited, and medical
problems are generally not increased compared to those
in the general population. As mentioned, skin cancers
may occur and regular skin checks should be offered.
Development and intelligence are normal. Persons with
OCA have normal fertility.

Acknowledgements
We thank Niels Bech, MD, for helpful communication concerning the clinical description. Regarding figure 2, written consent was obtained from the
patients or the patients' relatives'.

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TYPE Review
PUBLISHED 18 October 2022
DOI 10.3389/fpubh.2022.1028545

OPEN ACCESS

Rare disease emerging as a
global public health priority

EDITED BY

Chiuhui Mary Wang,
Rare Diseases International, France
REVIEWED BY

Daniel Wainstock,
Pontifical Catholic University of Rio de
Janeiro, Brazil
Thaisa Gois Farias de Moura Santos
Lima,
Ministry of Health, Brazil
Hugh Dawkins,
University of Notre Dame
Australia, Australia
*CORRESPONDENCE

Brian Hon Yin Chung
bhychung@genomics.org.hk
Annie Tsz Wai Chu
atwchu@genomics.org.hk
SPECIALTY SECTION

This article was submitted to
Public Health Policy,
a section of the journal
Frontiers in Public Health
RECEIVED 30 August 2022
ACCEPTED 30 September 2022
PUBLISHED 18 October 2022
CITATION

Chung CCY, Hong Kong Genome
Project, Chu ATW and Chung BHY
(2022) Rare disease emerging as a
global public health priority.
Front. Public Health 10:1028545.
doi: 10.3389/fpubh.2022.1028545
COPYRIGHT

© 2022 Chung, Hong Kong Genome
Project, Chu and Chung. This is an
open-access article distributed under
the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the
original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution
or reproduction is permitted which
does not comply with these terms.

Claudia Ching Yan Chung1 , Hong Kong Genome Project,
Annie Tsz Wai Chu1* and Brian Hon Yin Chung1,2*
1

Hong Kong Genome Institute, Hong Kong, Hong Kong SAR, China, 2 Department of Paediatrics and
Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of
Hong Kong, Hong Kong, Hong Kong SAR, China

The genomics revolution over the past three decades has led to great strides
in rare disease (RD) research, which presents a major shift in global policy
landscape. While RDs are individually rare, there are common challenges and
unmet medical and social needs experienced by the RD population globally.
The various disabilities arising from RDs as well as diagnostic and treatment
uncertainty were demonstrated to have detrimental influence on the health,
psychosocial, and economic aspects of RD families. Despite the collective
large number of patients and families affected by RDs internationally, the
general lack of public awareness and expertise constraints have neglected
and marginalized the RD population in health systems and in health- and
social-care policies. The current Coronavirus Disease of 2019 (COVID-19)
pandemic has exposed the long-standing and fundamental challenges of
the RD population, and has reminded us of the critical need of addressing
the systemic inequalities and widespread disparities across populations and
jurisdictions. Owing to the commonality in goals between RD movements
and universal health coverage targets, the United Nations (UN) has highlighted
the importance of recognizing RDs in policies, and has recently adopted
the UN Resolution to promote greater integration of RDs in the UN agenda,
advancing UN’s commitment in achieving the 2030 Sustainable Development
Goals of “leav[ing] no one behind.” Governments have also started to launch
Genome Projects in their respective jurisdictions, aiming to integrate genomic
medicine into mainstream healthcare. In this paper, we review the challenges
experienced by the RD population, the establishment and adoption of RD
policies, and the state of evidence in addressing these challenges from a
global perspective. The Hong Kong Genome Project was illustrated as a
case study to highlight the role of Genome Projects in enhancing clinical
application of genomic medicine for personalized medicine and in improving
equity of access and return in global genomics. Through reviewing what
has been achieved to date, this paper will provide future directions as RD
emerges as a global public health priority, in hopes of moving a step toward
a more equitable and inclusive community for the RD population in times of
pandemics and beyond.
KEYWORDS

rare disease, genomic equity, diversity, public health priority, inclusiveness, Hong
Kong Genome Project

Frontiers in Public Health

01

frontiersin.org

Chung et al.

10.3389/fpubh.2022.1028545

Introduction

Challenges experienced by the RD
population

Rare diseases (RDs) are an emerging public health priority.
RD refers to a disease that affects a small number of people in
a population (1). There are 6,000–8,000 unique RDs identified,
with approximately 80% being genetic in origin, and 50–75%
being pediatric onset (1–3). They are often chronic, progressive,
and debilitating, and can lead to significant morbidity and
mortality (4). With RDs’ nature being heterogeneous, complex,
and individually rare, they are difficult to be diagnosed, and are
challenging to be assessed in aggregate. Currently there is no
universal definition for RDs, with differing prevalence among
different parts of the world. The European Union Regulation on
orphan medicinal products defined RDs as conditions affecting
<50 per 100,000 individuals in the European population (5),
whereas the American Orphan Drug Act defined RDs as
conditions affecting <200,000 individuals in the United States
(6, 7). Other definitions have been proposed by different
jurisdictions, ranging from five per 100,000 to 76 per 100,000
individuals, with the global average being 40 per 100,000
individuals (Figure 1) (8–10).
Although individually rare, the collective number of people
affected by RDs was equivalent to the population of the world’s
third largest country (11). A recent global RD prevalence based
on 3,585 RDs was estimated to be 3.5–5.9% of the world’s
population, which corresponds to 263 to 446 million people
worldwide (10). When the impact of RDs extends to family
members and carers of the RD patient, it was expected that RDs
affect approximately 1.05–1.4 billion people globally (12).
Long diagnostic odyssey, lifelong disabilities, lack of
compensatory support, and few but costly effective treatments
are some of the unmet needs that plagues the lives of RD patients
(13, 14). The various disabilities arising from the disease as well
as diagnostic and treatment uncertainty have been demonstrated
to have detrimental influence on the health, psychosocial, and
economic aspects of the lives of the RD families (15, 16). In
2019, Rare Diseases International released a position paper
emphasizing the need for universal health coverage (UHC)
policies to account for RDs, owing to the commonality in goals
between RD movements and the UHC targets (17). The United
Nations (UN) political declaration on UHC has recognized
the RD population as a marginalized group that should be
considered during healthcare planning, claiming that UHC
“shall never be fully attained nor realized if persons living with
RDs are left behind and their needs left unmet” (17). Despite the
significant challenges faced, under allocation of resources and
inadequate healthcare planning for the RD population remains
prevalent (13).

While RDs are individually rare, there are common features
across the range of RDs and common challenges experienced
by the RD population. Unmet medical and social needs of
RD patients, families, and carers exist globally. Approximately
half of the individuals with suspected RDs are undiagnosed,
while RD patients who have received a diagnosis encounter
fundamental myriad challenges due to delays or incorrect
diagnoses, treatment, care, and social acceptance (18).
From the individual’s perspective, long diagnostic odyssey
often plagues the lives of RD patients. In Europe, 25% of
the RD patients had to wait between 5 and 30 years from
disease onset to receiving a genetic diagnosis for their condition,
and 40% had initially received multiple misdiagnoses, leading
to ineffective and unnecessary medical management (19). In
another survey of RD families from the United Kingdom and
United States, patients typically visit eight physicians and receive
two to three misdiagnoses prior to receiving a correct genetic
diagnosis, which spanned over a period of 5.6–7.6 years (2, 20).
Not only do the individuals endure years of diagnostic odyssey,
but it is also expensive for the health systems to undergo a
succession of unnecessary medical follow-ups and conventional
diagnostic approaches.
Undeniably, a genetic diagnosis offers the potential for
personalized medicine, yet opens another door of challenges
in treatment availability, accessibility, and affordability. With
RDs being heterogeneous and individually rare, interventions
and therapies, including orphan drugs, are seldom available
due to the lack of market incentives and small market
opportunity for the biopharmaceutical industry (21, 22).
Currently, <3% of diagnosed RDs have a suitable drug
treatment (21, 23); it was estimated that fewer than onetenth of RD patients have received disease-specific treatment
globally (24). Where a treatment has been approved for a RD,
cost of the drug is generally extremely costly, with RD drugs
reported to be as high as 13.8 times more than conventional
drugs (21, 23). This can be financially overwhelming for
many, especially when RD drugs usually require out-ofpocket (OOP) cost-sharing by the patient. Consequently, RD
patients may need to bear the catastrophically high OOP
expenditure on health services and resources, posing a higher
risk of financial hardship. For patients who are not able
to afford the extremely costly therapies, they will continue
to be managed with conventional approaches, adding to the
never-ending socio-economic costs of RDs. Accessibility also
remains to be a problem, with access and reimbursement
recommendations on the same intervention varying vastly
across jurisdictions.
From a wider socio-economic perspective, both patients
and carers have highlighted the challenges in maintaining

Abbreviations: NHGRI, National Human Genome Research Institute; NIH,
National Institutes of Health; RD, rare disease; RNA Seq, RNA sequencing;
WES, whole-exome sequencing; WGS, whole-genome sequencing.

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FIGURE 1

RD prevalence per 100,000 across jurisdictions [adapted from Richter et al. (9)].

Challenges in funding treatments and
therapies for RDs

employment and education due to frequent medical follow-ups
and the unprecedented and uncertainty nature of their
condition (25–28). In the United Kingdom, 66% of the
RD patients and carers indicated that their ability to hold
paid employment was affected, with many of them being
forced to retire early or reduce working hours due to
the condition or the related caring responsibilities (25).
Importantly, a significant number of RD patients and carers
were forced to reduce working days or quit their job
completely by their employer because they were considered
as “unreliable.” These ultimately manifest as significant
opportunities and productivity loss, and can be a burden
for the RD patients, families, and the society as a whole.
Due to social discrimination and stigmatization, low social
awareness, and lack of knowledge and understanding from
the general public, both RD patients and carers often feel
isolated and excluded from the society (29). As such, the RD
population experience extraordinary healthcare, psychosocial,
and economic burden, contributing to the decreased wellbeing
and quality of life.
Despite the collective large number of patients
and families affected by RDs internationally, the
general lack of public awareness and expertise
constraints have neglected and marginalized the RD
population in healthcare systems and in health- and
social-care policies.

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In the era of resource and budget constraints, health
economic evidence plays a critical role in guiding decision
makers to prioritize and allocate resources efficiently and
effectively. Although cost-effectiveness and cost-utility analyses
are often considered to be more useful in informing health
and social care decisions, as they take account into both
costs and outcomes simultaneously as compared to other
option alternatives, such types of analyses are relatively difficult
to be conducted within the RD population. This is due to
the limited intervention alternatives that are available in the
market, the small number of patients that can be recruited
into clinical studies, and the conflicting ethical considerations
for funding RD treatment (21, 22, 30, 31). Orphan drugs and
RD interventions are often considered to be cost-ineffective
against standard cost-effectiveness thresholds, such as the
£20k – £30k (US$26k–$39k) per quality-adjusted life year
(QALY) threshold proposed by National Institute for Health
and Care Excellence (NICE), due to treatment’s epidemiological
and economic specifics (31, 32). Future health technology
assessments concerning epidemiological, clinical, and economic
evidence are warranted for assessing and appraising RD
treatment and medications at a territory-wide or national
level (31).

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Genomic medicine challenges conventional health
economic evaluation paradigms, which fails to capture the
multi-dimensional outcomes that genomic medicine generates.
Some health economists and ethicists have argued for an
adjusted threshold for the RD population, such as the £78.3k
(US$102.4k) per QALY threshold at the RD mid-point
population and £937.1k (US$1,225.9k) per QALY for ultra-rare
orphan drugs, based on the principles of equity and “veil of
ignorance” (22, 33–35). Nevertheless, the adjusted threshold
does not fully encompass the challenges associated with
rarity. While the QALY can be a useful measure to evaluate
health-related quality of life and survival, its simplicity in
methodological calculation does not capture multi-dimensional
patient benefits. The QALY is only one of the many elements
of value in the “value flower” proposed by Lakdawalla et al.,
which could all contribute to how a healthcare intervention is
valued (36). Elements such as the severity of disease, insurance
value, real option value, and equity, are particularly relevant
and important for RD therapies and should also be considered
(37). Others have proposed that efficiency assessments such as
cost per QALY should not be employed when the alternative
choice is between an only treatment and no treatment (35). On
the other hand, the multi-criteria decision analysis approach is
proposed to provide more transparent and inclusive evidence
in identifying and combining the relative importance of
different criteria and stakeholder perspectives in a single
health technology assessment for RD therapies, with the aim
of balancing evidence among different stakeholders. More
recently, the new NICE methods and processes for technology
appraisals have been adopted in February 2022, with some of the
changes made of particular relevance to determining the value
of RD therapies. These include consideration of disease severity,
different types of evidence including qualitative and expert
elicitation, flexibility to accept uncertainty in specific situations,
and commercial and managed access. It is recommended
that NICE appraisals should consider the degree of need and
desirability to promote innovation in addition to the clinical
effectiveness and value for money. Health system’s obligations
for equality and human rights must also be considered.
Flexibilities should be adopted rather than strictly following the
cost-effectiveness threshold. These provide an innovative and
sustainable framework to assess and appraise RD interventions.
In the future, decision makers and health authorities should
take account into the spill over effect, the broader social value
of RD treatment and intervention, and their potential and
innovativeness for other non-rare cases (31).

confirmed and over 6.4 million deaths were reported across
222 jurisdictions since the outbreak of COVID-19 in December
2019 in Wuhan China (38). The pandemic has reminded us of
the critical need of addressing the systemic inequalities in the
determinants of health and illnesses, including genomic, social,
and environmental factors, which has resulted in widespread
disparities across populations and jurisdictions. This highlights
the paramount importance of engaging a more diverse and
inclusive research workforce, including the RD population.
The COVID-19 pandemic has further perpetuated and
exacerbated the unmet needs and challenges experienced by
the RD community, regardless of whether they were infected
with COVID-19.
First, RD has been identified as a risk factor for COVID-19
related mortality. While RD patients had a similar rate of
COVID-19 infection as the general population, Chung et al.
reported that RD patients were associated with an adjusted 3.4
times odds of COVID-19 related hospital mortality compared
to the general population in Hong Kong (95% CI 1.24–9.41;
p = 0.017) (39). Similar findings were observed in a retrospective
cohort study in Genomics England 100k Genomes participants,
in which RD patients were found to have a 3.5 times odds of
COVID-19-related deaths compared to the unaffected relatives
(95% CI 1.21–12.2), although the effect was insignificant after
adjusting for age and number of comorbidities (OR 1.94;
95% CI 0.65–5.80) (40). COVID-19-related mortality was not
confined to one specific group of RD patients, as suggested
by both studies. Results from these studies suggested that RD
as a group is a pre-existing comorbidity that is associated
with COVID-19-related mortality, and should be considered in
healthcare prioritization (39, 40).
In addition to RD patients who were infected with
COVID-19, patients without infection had also experienced
enormous and multifaceted challenges during the pandemic.
Interruptions of care, particularly delays and cessation of
diagnostic workups, therapies, rehabilitation, surgeries, and
medications, pose substantial impact on the health and social
wellbeing of the RD patients. Genetic laboratories and hospitals
were required to provide urgent services only, to focus
manpower and resources on combating COVID-19. In the
United Kingdom, referrals to Clinical Genetics Service fell
over 50% during April to June 2020 as compared to the
same period in 2019 (41). Request for genetic testing such as
microarrays, which is often the first line genetic diagnostic test
for patients with suspected undiagnosed genetic disease, was
markedly reduced (41). There was also substantial decrease
in the number of other diagnostic tests performed, including
echocardiograms, radiological investigation, and gastroscopies
(41). The pandemic has disproportionately exacerbated the
problem of diagnostic delay for RDs, affecting all points on
the path to diagnosis, from initial engagement with health
services, referral for investigation or specialist assessment, to
the availability of definitive testing and registering with patient
advocacy groups for support. In addition to the significant drop

RDs under the COVID-19 pandemic
The current Coronavirus Disease of 2019 (COVID-19)
pandemic remains to be an unprecedented global health
challenge due to its persistent spread and unpredictable clinical
course. As of August 23, 2022, over 595.1 million cases were

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in RD diagnosis, health service utilization was also substantially
affected. In Hong Kong, over 70% of the RD patients had reduce
health service utilization during the pandemic (42). Importantly,
health status was affected in 46% of the patients due to reduced
service provision. Psychological health and rehabilitation were
affected in 79% and 78% of the patients respectively, especially
among patients who are severely or totally dependent according
to the Barthel Index for Activities of Daily Living (42). Moreover,
patients’ social life, daily living, and financial status were
also severely impacted by the COVID-19 pandemic, affecting
92%, 89%, and 81%, respectively (42). Almost 60% of the
patients reported increased expenditure during the pandemic,
while 56% of the patients experienced reduction in household
income, indicating the magnified financial burden on the RD
population (42). Similar patterns were also identified in other
cohorts in the West, all highlighting the significant repercussion
of the pandemic on regular healthcare service, physical and
psychological health, and financial status of the RD population
(43–47). The COVID-19 pandemic has inspired and accelerated
the adoption of telemedicine and telehealth in some parts of the
world (43, 48). Future implementation of telemedicine into the
healthcare systems may serve as a sustainable healthcare delivery
model beyond the COVID-19 pandemic.
For carers of the RD patients, lifelong caring has posed
substantial psychological and financial burden in the best of
times, and these challenges have been further exacerbated during
the COVID-19 pandemic. In a study by Fuerboeter et al. to assess
the mental health and overall quality of life in parents of children
with rare congenital surgical diseases in Germany, the parents,
especially mothers, reported severe psychosocial impairment
during the pandemic (49). Parents of the RD patients had a
significantly lower quality of life than parents in the control
group, potentially due to the lockdown measures imposed,
daily care for the patient, work-from-home measures, and the
concerns of their children being at a higher risk of infection
after surgeries (49). This study highlighted the need to provide
support and raise awareness for parents in addition to the
RD patient via a family-centered approach, especially during
difficult periods such as the era of COVID-19 pandemic.
Besides RD patients and carers, the pandemic has also
brought unprecedented challenges to RD patient organizations
internationally. A multinational cross-sectional study was
conducted to evaluate the impact of the COVID-19 pandemic
on 80 RD organizations across 10 jurisdictions in the Asia
Pacific region, namely Australia, Hong Kong, India, Japan,
mainland China, Malaysia, New Zealand, the Philippines,
Singapore and Taiwan (48). The study found that almost 90% of
the patient organization representatives were concerned about
the pandemic’s impact on their organizations. In particular,
over 60% and over 40% of the participants have highlighted
reduction in organization capacity and funding as their biggest
challenges during the pandemic respectively (48). They have
also experienced difficulties in supporting their members as
physical interactions were restricted. Importantly, patient group

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representatives underpinned the need to move toward a
digitalised era, both in organization operation and healthcare,
especially amidst confinement measures. In particular, operation
of RD patient organizations in Australia and New Zealand
were not impacted or were less affected by the pandemic as
they had greater digital capacities and have digitalised their
operations prior to the pandemic (48). The pandemic has
brought myriad challenges to the RD patients and organizations,
yet has also created opportunities by accelerating the adaption of
tele-operation and telehealth, complementing face-to-face visits
and consultations.
The current COVID-19 pandemic has highlighted and
exposed the long-standing and fundamental challenges and
healthcare needs of the RD population. The healthcare, social
care, economic, and organizational challenges experienced
by the RD community indicate the importance of ensuring
adequate and continuity of diagnostic and priority management
strategies for RDs during pandemics and beyond.

RDs: A global public health priority
The challenges arising from the nature of RDs have
led RDs to emerge as a global public health priority.
Unprecedented global integration of RD research is crucial to
raise awareness, enhance understanding, accelerate diagnosis,
and improve treatment for RDs. Recognizing its importance,
the International Rare Diseases Research Consortium
(IRDiRC) was established in 2011 to facilitate international
collaboration between public and private sectors, and among
stakeholders active in RDs research across government research
funding bodies, companies, academia, and patient advocacy
organizations around the world (50, 51). The IRDiRC have
set out three 10-year goals for 2017 to 2027, with the vision
to enable RD patients to achieve an accurate diagnosis, and to
receive appropriate care and available therapy within 1 year of
seeking medical attention (50). The three IRDiRC goals are:
• To provide all individuals with suspected RDs who have
seek medical attention with a diagnosis within 1 year if
the RD is reported in medical literature; and to put those
who remain undiagnosed in an international coordinated
diagnostic and research pipeline;
• To approve a thousand new therapies for RDs, with the
majority focusing on RDs without approved options; and
• To develop new methodologies for assessing the impact of
RD diagnoses and therapies.
The three IRDiRC goals mainly target the healthcare
challenges of RDs, with the overarching aim being to galvanize
the broad RD community to enable universal diagnosis and
treatment, to ensure that the programmes and interventions
can reach RD patients and families, and to pose the intended

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Improving RD diagnoses and its
implications

positive impact on the health and wellbeing of the RD
population (50, 51).
Recognizing the importance of promoting inclusion and
protecting the human rights of the RD population, EURORDIS,
Rare Disease International, and the Committee on NonGovernmental Organizations (NGOs) for RDs, together called
for a UN Resolution for RDs in 2019, urging the 193 UN
Member States of the General Assembly to adopt the Resolution
by the end of 2021. This campaign targets the RD patients
and families by recognizing and addressing their needs and
challenges, which aims to promote greater integration of RDs
in the agenda of the UN, and advances UN’s commitment in
achieving the Sustainable Development Goals (SDGs) of the
2030 Agenda, with the endeavor to “leave no one behind.” The
UN resolution has five key asks:

Traditionally, making a diagnosis is particularly challenging
due to the heterogeneity and the rarity of each of the
6,000–8,000 RDs, multisystemic involvement, and pleiotropic
manifestations (53–55). In the era of genomic medicine, our
understanding on RDs has been transformed by the rapid
expansion and translational application of next-generation
sequencing (NGS) technologies in the past decade. NGS
technology utilizes massively parallel sequencing methods to
simultaneously and comprehensively sequence multiple genes,
the entire protein-coding region of the genome (the “exome”),
or the entire human genome (56). The diagnostic capacity of
whole-exome sequencing (WES) and whole-genome sequencing
(WGS), both NGS approaches, were shown to be effective over
conventional diagnostic approaches across multiple studies in
different populations. In a meta-analysis including 37 studies
and comprising 20,068 children, the pooled diagnostic rates
among WES and WGS were found to be 0.36 (95% CI
0.33–0.40, I 2 = 83%) and 0.41 (95% CI 0.34–0.48, I 2 =
44%), respectively, higher than the conventional diagnostic
method of chromosomal microarray (0.10, 95% CI 0.08–0.12,
I 2 = 81%) (57). In critically ill patients with urgent needs,
previous clinical studies have illustrated the vast amount of
potential of rapid WES (rWES) and rapid WGS (rWGS) in
diagnostic capacity, speed, and clinical utility in acute care
(53, 58–60). The diagnostic capacity of rWES and rWGS was
corroborated by findings from 18 studies comprising 1,049
patients from different countries, combined as part of a metaanalysis, with the pooled diagnostic yield being 0.43 (95% CI
0.36–0.50, I 2 = 80.7%) (61). The successful application of WES
and WGS in diagnosing patients with RDs in different settings
has also allowed new gene discoveries over the years since its
introduction in 2010 (Figure 2) (62, 63). The speed of new gene
discoveries has been increasing substantially, with discoveries
made by WES and WGS almost tripled the discoveries made by
conventional methods since 2013 (62).
More importantly, WES and WGS offer the potential for
the development of pragmatic, phenotype-driven management
with genotype-differentiated personalized treatment (64).
Personalized medicine, according to the National Human
Genome Research Institute (NHGRI), was defined as an
emerging practice of medicine that utilizes an individual’s
genetic profile to guide clinical decision-making in disease
prevention, diagnosis, and treatment (65). WES and WGS
have the potential to impact diagnosis-predicated clinical
management, often referred as clinical utility, which includes
but not limited to referral to specialists, surveillance for
potential future complications, lifestyle changes, and indication
or contraindication of investigations, procedures, surgeries,
and medications (61, 66). In the meta-analysis by Clark et al.
that included four WGS studies and 12 WES studies with

• Social inclusion and participation of RD patients
and families;
• Universal and equitable access of quality healthcare without
having to experience financial hardship;
• Promotion of RD strategies and actions at a national level;
• Integration of RDs into UN programmes, agencies, and
priorities; and
• Routine publication of UN reports for resolution
progress monitoring.
The Call for UN Resolution has promoted research and
global coalition to tackle the socio-economic challenges of the
RD population. The UN resolution was subsequently adopted on
December 16, 2021 (52); this is an important milestone toward
greater awareness and recognition for the RD community,
allowing implementation of international policies to address the
needs and challenges of the RD population.

The state of evidence in addressing
the challenges of the RD population
National and international stakeholders across academia,
health systems, governments, funding bodies, NGOs, and
patient advocacy organizations have set out research projects
and programmes to tackle the challenges experienced by the RD
population, contributing to achieving the three IRDiRC goals
and the five UN Resolution key asks. There has been tremendous
progress in RD research over the past decade, especially in RD
diagnoses and gene discoveries, achieved by the advancement in
genomic technologies. Positive trend in RD-related therapeutic
development was also observed, with the IRDiRC’s 2020 goal
for 200 new therapies being achieved in early 2017, three years
ahead of the agenda (50). The socio-economic burden of RDs
is harder to gauge and is rather limited in literature, given the
collective number of unique RDs identified and the lack of
standardized methodologies to collect related data.

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FIGURE 2

Number of gene discoveries made by WES/WGS compared with conventional diagnostic methods [adapted from Chong et al. (62)].

data on clinical utility, 27% (95% CI 17–40%, I 2 = 54%) and
17% (95% CI 12–24%, I 2 = 76%) of children with genetic
diagnoses had subsequent changes in their clinical management
respectively (57). Early and rapid adoption of rWES or rWGS
within a median of two to three weeks of results turnaround
time could potentially impact clinical management promptly
and profoundly, thus improving patient’s clinical outcome
and quality of life, and reducing morbidity and mortality
(58–60, 67). In the intensive care setting of the National
Health Service (NHS) of the United Kingdom, the use of
rWGS led to changes in clinical management in 65% of the
diagnosed patients (60). Chung et al. investigated the diagnostic
utility of rWES and rWGS as a meta-analysis, and illustrated
that genetic diagnoses could impact clinical management
in up to 100% of the diagnosed patients in some cohorts
(61). A rapid and timely genetic diagnosis is particularly
important among critically ill patients with urgent needs, as it is
potentially lifesaving.
The implication of RD diagnoses is beyond that on
patients. In the era of resource and budget constraints,
the evaluation of economic implications of providing WES
and WGS within clinical settings has a principal role in
informing efficient and effective healthcare resource allocation.
Despite the high unit costs of WES and WGS, studies have

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demonstrated the cost-effectiveness of WES and WGS across
clinical settings (68–72). On the other hand, health-economic
evidence of rWES and rWGS is rather limited, with the fact
that parallel comparison of rWES/rWGS and conventional
diagnostic methods is more challenging due to the critical
and urgent clinical setting that requires immediate clinical
management decisions. Studies however illustrated the potential
of rWES and rWGS to reduce healthcare costs, with costs
being saved in the avoidance of unnecessary investigations,
procedures, hospitalisations, and medications (58, 59, 61). In
particular, Stark et al. reported a cost-saving of AU$543,178
(US$408,090) from avoidance of planned procedures and
hospital days using rWES in Australia (59). In Hong Kong,
Chung et al. demonstrated a reduction of 566 hospital days and
a cost-saving of HK$8 million (US$1.03 million) from clinical
management changes using rWES (61). In the United States,
Farnaes et al. illustrated a net cost-saving of US$128,555 from
reduced inpatient days using rWGS (58). Available evidence
shed light on the consideration of integrating WES/WGS into
clinical workflows to enable precision medicine and reduce
healthcare costs.
The importance of an early genetic diagnosis for RD
patients was demonstrated and highlighted in many of the
previous studies, contributing to and reinforcing the 10-year

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data beyond health administrative dataset for the RD population
(15, 75).
The largest study to date, estimated healthcare utilization
and related costs across 1,600 RDs from a health system
perspective in the United States. The study highlighted
the disproportionately higher number of inpatient stays,
readmissions, emergency visits, and the related costs of the
RD population as compared to other common conditions
(76). Similarly, the direct immediate healthcare burden of RDs
was also estimated in studies conducted in Australia, Hong
Kong, Shanghai, and Taiwan (77–81), suggesting the high direct
healthcare costs in the RD population.
Although often neglected and rather challenging to estimate,
it is also extremely important to evaluate and estimate the
direct non-healthcare and indirect economic consequences
for healthcare and related planning, especially in a chronic
disease population. With RDs often being medically devastating
and life-threatening, unpaid informal carers, usually a family
member or a friend of the patient, play an extremely important
role in supporting and assisting the patient’s daily healthcare
and social needs. This harbors a unique set of challenges and
burden in RD carers, which encompasses coordination of care
as well as helping with daily activities, both of which have
spill over effects onto the carers’ own personal lives, especially
work responsibilities. The nature of RDs thus potentially
inhibits patient’s and carer’s participation and integration into
society, resulting in significant productivity loss, posing financial
constraints for the RD family in addition to the substantial
medical costs that often requires cost-sharing by the patient (82).
On the other hand, many of these carers, usually both parents of
the patients with RDs, have to sustain family’s financial income
by staying in the workforce. Therefore, paid carers, such as
live-in domestic helpers, are commonly hired as an alternative
to provide formal care support. This is particularly prevalent in
Asia, such as the case in Hong Kong. In fact, previous evidence
has demonstrated that direct non-healthcare and indirect costs
of RDs (including paid and unpaid carers) are higher than direct
healthcare costs of RDs, reflecting the importance to consider
the broader socio-economic consequences of RDs in health- and
social-care policies (16).
As highlighted by a meta-analysis published in 2021 that
identified 19 studies in literature, economic evidence from a
wider societal perspective has been very limited, with majority
of the evidence focusing on individual RDs (75). Almost
all of the identified studies were conducted in European
populations, with many of them collected as part of the “Social
Economic Burden and Health-Related Quality of Life in Patients
with Rare Diseases in Europe” (BURQOL-RD) project series,
which estimated the costs of 10 relatively “common” RDs
across eight jurisdictions in Europe (15, 83–92). The results
undoubtedly aided understanding on the patterns of resource
use and areas that require prioritization, supporting appropriate
healthcare planning for these 10 RDs. Nevertheless, the 10

FIGURE 3

Benefits of an early genetic diagnosis [adapted from Tan
et al. (73)].

goal of IRDiRC to provide an early definitive molecular
diagnosis within 1 year of medical attention (50, 63). An
accurate genetic diagnosis is the first step in managing the RD
properly, allowing the identification of useful resources and
treatment for the best possible clinical outcome for patients.
The diagnosis-predicated changes in management not only
improved clinical outcomes for patients, but could also lead to
net cost-savings, stressing its multi-level significance. In addition
to the immediate clinical changes and associated cost-savings
from a rapid genetic diagnosis, an early genetic diagnosis has
the power to aid better understanding in RD epidemiology
and target health disparities, which all act as strong advocacies
for the RD population (Figure 3) (73). It also contributes to
existing literature and provides empirical evidence for better
health- and social-care planning, such as implementation of
population-wide sequencing and prevention strategies (74).

Socio-economic costs of RDs
The societal impact of RDs has an economic dimension.
In literature, majority of the economic evidence was based
on individual RDs that are relatively “common,” while recent
studies accounting for a wider range of RDs often quantify
direct healthcare costs from a health system perspective due to
the lack of standardized methodologies to collect cost-related

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to the general population (15, 28, 95, 96). In particular, the metaanalysis by Ng et al. included four studies comprising 2,079 RD
patients and demonstrated a pooled utility score of 0.57 (95%
CI 0.48–0.66), consistently lower than that of the general public
(95). Importantly, Ng et al. has also demonstrated the “spill over
effects” on carers’ HRQoL in Hong Kong. Lifelong caring, high
dependency of patient, and economic strain are all factors that
contribute to the decreased wellbeing of patient family members
and carers. In Hong Kong, both RD patients (mean utility score
of 0.53) and their carers (mean utility score of 0.78) reported
lower utility scores than the general population (mean utility
score of 0.92) (95). More strikingly, they reported utility scores
even lower than that of patients with other chronic illnesses,
including patients with heart disease (0.88), hypertension (0.88),
diabetes (0.87), and cancer (0.87), reflecting the disproportionate
impact of RDs on healthcare and social wellbeing (95, 97, 98).

selected RDs may be insufficient to encompass the heterogeneity
and differential impacts of the 6,000–8,000 known RDs. It is
important to note that the economic impact of RDs that are
relatively “rare” was never reported in literature, due to the
challenges in patient recruitment. Recently, the EverydayLife
Foundation has published a report that estimated the costs of
379 RDs in the United States from a societal perspective, which
was found to be US$62,141 per patient per year (16). In 2019,
the national cost of RDs in the United States totalled US$966
billion (non-healthcare and indirect costs accounting for 56.7%),
significantly higher than the costs estimated for some of the
most expensive chronic illnesses, including cancer, diabetes, and
heart disease as indicated by the Centers for Disease Control and
Prevention (CDC) (16). Although only 379 of the 6,000–8,000
RDs were included for estimation, to the best of knowledge,
this represents the only and the most comprehensive study to
evaluate the socio-economic burden of RDs as a collective group.
In addition to the high societal costs of RDs, it was
anticipated that the disproportionately high service and resource
needs, and the RD-related productivity loss might pose
significant financial burden on the RD families, putting them at a
higher risk of experiencing financial hardship. Only two studies
have attempted to evaluate the proportion of financial hardship
brought about by extremely high OOP health expenditure
in the RD population to date, one being in China where
the authors have estimated the rate of catastrophic health
expenditure (CHE) across seven RD groups (93), and another
study being in Turkey where the authors estimated the CHE
incidence mainly in patients with metabolic and neuromuscular
diseases (94). These two studies have reported very different
rates of CHE at different thresholds (0.0015–0.1670% vs.
47.35%), reflecting the differences in healthcare and social
care contexts, and the availability and accessibility of resources
across jurisdictions.

The role of Genome Projects in
advancing genomic medicine
The importance of generating greater representation and
diversity across genomic datasets is becoming more widely
recognized. Initially, genetic research and genomic databases
were biased toward data from Caucasians, particularly of
European ancestry. In 2009, 96% of genome-wide association
studies were of European descent (99). Groups of other
ancestries were very poorly represented. The lack of ethnic
diversity in genomics was limiting the usefulness of genomic
technologies and widening inequalities across different
populations. To address this, contribution of genomic data
of other ethnicities has increased over the past few years,
increasing from 4% in 2009 to 19% in 2016 (99).
Besides research, governments have also started to launch
Genome Projects in their respective jurisdictions to apply
WGS to the study of RDs, and to a lesser extent, cancers
and common disorders, at a much bigger population size, or
even at a nationwide level, to integrate genomic medicine into
mainstream healthcare and to improve global genomic diversity
and equity (100).
The government of the United Kingdom has launched the
100,000 Genomes Project in 2013, and it has been a huge
success in providing grounds for the NHS Genomic Medicine
Service to be the first national health care system to offer WGS
as part of routine clinical care for patients with undiagnosed
RDs and cancers (101, 102). This has inspired governments
worldwide, even in middle-income countries, to launch Genome
Projects in their respective jurisdictions, aiming to enhance
clinical application of genomic medicine for personalized
medicine (Figure 4) (100, 103). In the upcoming years, results
from Genome Projects worldwide would potentially enhance
our capability to better diagnose and manage RDs, and
would provide empirical evidence for implementation of

Health-related quality of life of the RD
population
The impact of RDs can also be determined by quantifying
patient’s health-related quality of life (HRQoL). HRQoL is
defined as “an individual’s perception of his/her living quality,
encompassing physical, mental, and social wellbeing” (95). Most
RDs are typically chronic, progressive, degenerative, and lifethreatening, with effective drugs being costly and scarce. Social
exclusion and discrimination based on RD health conditions
further depletes available resources for coping with RDs (27).
It is therefore crucial to identify and understand the impact of
disease and social related difficulties on the quality of life of
RD patients. Previous studies have attempted to investigate the
HRQoL of the RD population in more than one RD group, and
have highlighted the significantly lowered HRQoL as compared

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FIGURE 4

Large-scale Genome Projects targeting RDs and undiagnosed diseases (>20,000 subject genomes) (i) (104, 105); (ii) (106); (iii) (107); (iv)
(108, 109); (v) (110); (vi) (111); (vii) (112); (viii) (113, 114); (ix) (115); (x) (116, 117); (xi) (118, 119); (xii)(101, 120); (xiii) (121, 122); (xiv) (123); (xv) (124).
[adapted from Chung et al. (100) and Chu et al. (103)].

Project (HKGP) was selected to illustrate the contribution of
Chinese genomic data.
In the 7.5 million population in Hong Kong with 94%
of the population being Chinese (ethnically speaking, Han
Chinese), one in 67 individuals is living with one or more
RDs, with 35% being pediatric patients (78, 125). As of 2018,
over 470 RDs have been identified in Hong Kong, affecting
approximately 1.5% of the population (78). In order to enhance
clinical application of WGS to benefit patients and families,
particularly the RD population, and to strive for excellence and
adherence to international standards, the Hong Kong Genome
Institute (HKGI) was established in May 2020 by the former
Food and Health Bureau (currently the Health Bureau), Hong
Kong Special Administrative Region, to implement the HKGP,
with the vision being “to avail genomic medicine to all for better
health and wellbeing” (126).

WES/WGS in health systems. More importantly, genomic data
across populations, especially those beyond Europe and North
America, will together contribute to improving equity of access
and return in global genomics.

Case study: The Hong Kong Genome
Project
As discussed above, genomic data of non-European
ancestries has been increasing over the years. Genome Projects
in Asia for example, are playing a major role in contributing
genomic data of Asian ancestry to improve global genomic
diversity. In Asia, Hong Kong has a relatively homogeneous
Chinese population. The case study of the Hong Kong Genome

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The HKGP, which is implemented in two phases, the pilot
phase and the main phase, is the first large-scale genome
sequencing project in Hong Kong. It is set to conduct WGS
for 20,000 cases with the aim to enhance clinical application
of genomic medicine to benefit patients and their families with
more precise diagnoses and personalized treatment (126). The
pilot phase of the HKGP was launched in July 2021, focusing
on undiagnosed diseases and hereditary cancers. Lessons learnt
during the pilot phase of HKGP would guide the directions of
the Project’s main phase, which is set out to be rolled out in July
2022, expanding eligibility to cover other hereditary diseases and
research cohorts related to “genomics and precision health.”
With WGS being offered as part of the HKGP, it could
potentially lead to diagnosis-predicated precision medicine for
patients and families, thereby improving patient outcomes
whilst minimizing healthcare expenditure and related financial
hardships, achieving diagnostic, clinical, and economic utility.
In addition to the clinical benefits, the HKGP also aims to
advance research, establish infrastructure and protocols, nurture
talents, enhance public genomic literacy and engagement, and
drive health- and social- care policy measures to pioneer the
development of genomic medicine in Hong Kong (126). The
potentials and prospects that have emerged in the launching of
the HKGP pilot phase were highlighted by Chu et al., providing
insights to prepare for the launching of the main phase (103).
With HKGP being the first and the largest local clinical genomic
database, it creates novel research opportunities for studying
various diseases, including RDs, contributing to improving
genomic equity in healthcare. With a relatively homogenous
population, genomic data generated from the HKGP would
contribute to global genomic diversity in the foreseeable future.

the implementation of education and training programmes,
elimination of discrimination and stigmatization, and global
coalition among multi-disciplinary stakeholders.
Firstly, providing education and training to clinicians at
the primary, secondary, and tertiary care level is the first step
to an accurate genetic diagnosis. Despite the technological
advancement and increased data sharing, many RD patients
still experience extensive diagnostic odysseys, and some remain
undiagnosed. One of the major barriers to obtaining a diagnosis
is the lack of knowledge and insufficient training on RDs.
According to the National Organization for Rare Disorders
(NORD) survey 2019, almost half of the patients and carers
identified limited medical specialization to be a major barrier
to delays in RD diagnosis (127). Previous studies have shown
that many primary care physicians profess low confidence in
their skillsets in managing patients with genetic-related issues
and in using genetic information to make clinical decisions
(128–131). Primary care physicians have identified lack of
knowledge and training opportunities to be the major barriers
to genomic medicine in primary care (128, 131, 132). Emphasis
on further education and training in genomic medicine among
medical specialists should be prioritized in order to improve
RD diagnosis and management. Continuous technological
and technical advancement in genomics is also required to
diagnose patients and to transform sequencing information into
diagnostic knowledge, such as the application of bioinformatics,
analytic algorithm, functional analysis, health informatics, data
linkage capability, data sharing, etc. (74, 133). Global network
involving full participation by clinicians, researchers, and
patients and carers should be formed to tackle the undiagnosed
cases (74). International efforts have been made over the years
to investigate and diagnose patients who had long sought one
without success, such as the initiation of the Undiagnosed
Disease Program by the National Institutes of Health (NIH)
and the Undiagnosed Diseases Network International (134, 135).
The establishment of these programmes and networks have
supported global improvements in diagnosis of RDs via core
principles and implementation methods (74).
Secondly, in addressing the significant socio-economic
burden and the lowered HRQoL of the RD population, the
government and healthcare system should work together to
provide affordable and accessible resources, thereby improving
the HRQoL of patients and carers. Previous cost-of-illness
studies highlighted the unique and complex challenges the RD
population face, providing strong evidence that management
of these challenges should be treated differently to other
common disease (15, 16, 77–79, 83–92). With RD patients
requiring services and care across multi-disciplines, patients
often experience frustration in service fragmentation. The
implementation of “one-stop” clinics may improve coordination
of care through providing various services at a single location,
tackling multiple and complex problems simultaneously (29). In
France and the United Kingdom, the integration of “one-stop”
clinics was shown to improve coordination between services,

Future directions of RDs
With the three 10-year goals laid out by IRDiRC and the
adoption of the UN Resolution in December 2021 to stress the
importance of including RD population in the UN 2030 Agenda,
great strides have been made in RD research over the past
decade, presenting a major shift in the global policy landscape.
In particular, previous studies have highlighted the importance
of an early diagnosis and the significant consequences of RDs
on the living quality and socio-economic burden of patients.
It should be recognized that the health, social, and economic
implications of RDs are inherently the results of insufficient
social support, limited medical expertise, and the lack of
public awareness on RDs. As RD emerges as a global public
health priority, RD policies and strategies in the sectors of
healthcare, social care, insurance, education, and many more,
are required to foster a more equitable and inclusive community
for the RD population. Progress in RD research and analysis
will likely improve all disease understanding in the future.
Here, we recommend future action plans for RDs through a
patient-centered and multidisciplinary approach, focusing on

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providing timely and informed care to the RD population
(136). Overall, the utilization of such “one-stop” clinics have
yielded better patient outcomes and are more cost-effective
and thus, are a possible solution to the high socio-economic
burden and the lowered HRQoL of RDs (137). In addition,
implementation of reimbursement regulations would improve
affordability and accessibility of treatments, potentially reducing
the risk of financial hardship of the RD population (138). Other
action plans in Australia and New Zealand have also been
put forward to support the RD population (139). These aim
to reduce the healthcare, social care, and economic burden
through empowering, improving diagnosis and intervention,
coordinating care and increasing research for RDs.
Thirdly, the government plays a pivotal role in raising
awareness and in mitigating discrimination and stigmatization
of the RD population. Efforts have been made in different
parts of the world to implement Genome Projects to integrate
genomic medicine in mainstream healthcare. In order to
enhance understanding and mitigate genetic discrimination,
unprecedented global coalition is of paramount importance to
improve inclusivity of the RD population. Previous studies have
demonstrated participants’ concerns on genetic discrimination
in the context of employment and insurance (140–142). In
particular, undergraduates in Hong Kong were found to be
pessimistic toward unfavorable genetic testing results, with
almost 60% of the respondents claiming that they would feel
“inadequate or different,” 56% would feel helpless, and nearly
60% perceived that they would be disadvantaged in job seeking
in case of unfavorable genetic testing results (140). It is of utmost
importance to eliminate the root causes of stigmatization and
discrimination of the RD population in order to improve social
inclusion and reduce opportunities and productivity loss. This
can be done through the implementation of anti-discrimination
policies such as Genetic Information Nondiscrimination Act
(GINA) in the United States to aid assimilation of the RD
population into society (143, 144). Legislations in Japan and
Taiwan have also incorporated social care services into their
RD framework, thereby facilitating the inclusion and integration
of the RD population into the society in addition to providing
quality healthcare (145). Additional education and awareness
for the public on the RDs should also be implemented to
increase acceptance and reduce stigma. Both these strategies
in conjunction will work toward improving social integration
of the RD population, thereby improving their HRQoL and
reducing socio-economic burden.
Fourthly, a more widespread utilization of telehealth or
telemedicine constitutes a sustainable and alternate model
amidst the COVID-19 pandemic and beyond. Telemedicine
has the potential to revolutionize patient access to clinical
specialists around the world without geographical boundaries.
The COVID-19 pandemic has accelerated the digitalisation
of healthcare across the world and have inspired healthcare
professional licensing agencies to address this in various nations
and states. This improves access for all patients in both urban

Frontiers in Public Health

and rural areas, and in both developed and developing countries
regardless of their economic status. Adoption of telemedicine
into routine clinical care would require innovative approaches
to increase capacity and the strengthening of health systems. In
the long run, greater reliance on telemedicine is undeniably the
way forward, which constitutes a sustainable healthcare delivery
model in times of and beyond pandemics.
Finally, RD patient organizations have the power to
drive forward the adoption of necessary policies and help to
coordinate care (146). Governments should strive to strengthen
the public’s awareness on the needs of RD populations
through in-depth conversations and focus group meetings with
patient representatives. On one hand, RD patient groups have
important roles in advocating for patients’ rights and research
opportunity. On the other hand, patient groups are the pillar
of psychologic support for patients and their families. The
recently adopted ground-breaking UN Resolution led by Rare
Disease International, EURORDIS, and the Committee on
NGOs for RDs serves as a strong example. It represents a
major shift in the global policy landscape, by promoting greater
integration and prioritization of the RD population in the UN
agenda. Through this global campaign, the needs of the RD
community are brought to light, allowing for the development
of necessary strategies and plans to provide affordable and
accessible care. Acting as the voice of the RD population, RD
patient organizations can empower patients and carers alike
while raising awareness to educate the community.
Taken collectively, there is a scientific, social, ethical,
and political imperative to promote greater integration and
inclusiveness of RDs in research and policies, contributing to the
goal of the UN Resolution, to “leave no one behind.”

Author contributions
CC and BC contributed to the conception of the review.
CC performed the literature review and drafted the manuscript.
Hong Kong Genome Project, AC, and BC critically reviewed
and revised the manuscript for important intellectual content.
AC and BC oversaw and supervised the review. All authors
contributed to the overall interpretation, reviewed, and
approved the final draft for submission.

Acknowledgments
We would like to thank all members of the Hong Kong
Genome Institute in preparing the launch of the Hong Kong
Genome Project. This work would not have been possible
without the instrumental leadership and guidance from Dr.
Su-vui Lo, Chief Executive Officer. We extend our gratitude
to the Board of Directors and Advisory Committees for their
continuous support and advice. We also wish to acknowledge
the support of the Hong Kong Genome Project stakeholders:

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Publisher’s note

the Health Bureau; Hospital Authority; and the Department
of Health.

All claims expressed in this article are solely those
of the authors and do not necessarily represent those
of their affiliated organizations, or those of the publisher,
the editors and the reviewers. Any product that may be
evaluated in this article, or claim that may be made by
its manufacturer, is not guaranteed or endorsed by the
publisher.

Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.

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