An Overview of Mendelian Disorders In

Saudi Arabia
Ahmed Alfares1, Fowzan Alkuraya2
1
Department of Paediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia
2
King Faisal Specialist Hospital and Research Center Riyadh, Riyadh, Saudi Arabia

‫نبذة مختصرة‬

‫ وهي المشتقة‬،‫المملكة العربية السعودية هي أكبر دولة في شبه الجزيرة العربية وهي تتبع الشريعة اإلسالمية‬
‫ ترتفع نسبة زواج األقارب في المملكة كما تنتشر اضطرابات وراثية معينة في فئات‬.‫عن المبادئ الدينية لإلسالم‬
ً
‫خصوصا في مناطق وقبائل‬ ،‫ يالحظ وجود مورثات خاصة بالمجتمع السعودي‬،‫ عالوة على ذلك‬.‫سكانية محددة‬
‫ والجلوكوما‬،‫ واإلعاقة الذهنية‬،‫ ومنها أمراض الدم‬،‫بشكل خاص‬
ٍ ‫ كما وترتفع نسبة بعض االضطرابات الوراثية‬.‫محددة‬
‫ أعلنت المملكة العربية السعودية عن إطالق برنامج الجينوم البشري‬،٢٠١٣ ‫ في عام‬.‫ وفقدان السمع‬،‫الخلقية‬
‫السعودي الذي يهدف إلى توثيق مائة ألف جينوم في المجتمع السعودي من أجل إجراء بحوث بيولوجية طبية ذات‬
‫ لتحديد األساس الجيني لألمراض الوراثية في المجتمع السعودي والتخفيف‬،‫جودة عالمية ترتكز على علم الجينوم‬
‫ يستعرض هذا الفصل االضطرابات الوراثية الشائعة في المملكة العربية السعودية وتأثير‬.‫من عبئها على أفراده‬
.‫التقاليد الثقافية على المجتمع‬

Abstract

The Kingdom of Saudi Arabia is the largest country of the Arabian Peninsula and it follows Sharia or Islamic
law, which is derived from the religious precepts of Islam. Consanguinity and high incidence of population-
specific disorders are well-known observations in Saudi Arabia. Furthermore, there are novel genes in the
Saudi population and founder effect is observed in specific tribes or regions. On the other hand, there are
commonly encountered genetic disorders in the Saudi population like hemoglobinopathies, intellectual
disability, congenital glaucoma, ciliopathies, inborn errors of metabolism disorders, retinal dystrophies,
3 hearing loss and primary microcephaly. In 2013, Saudi Arabia announced the launching of the Saudi Human
Genome Program which aims to sequence 100,000 human genomes to conduct world-class, genomics-based
biomedical research on the Saudi population, in order to provide a better understanding of the landscape
of genetic disorders in Saudi Arabia and challenge the burden to the community of inherited disorders. This
chapter reviews the genetic disorders in Saudi Arabia and the impact of cultural tradition on the community.

Introduction
The Kingdom of Saudi Arabia was established in hospitals, universities and the private sector. In
in 1932 by its founder King Abdulaziz ibn June 2016, the Saudi Council of Ministers approved
Abdulrahman Al Saud, uniting four distinct regions the National Transformation Program, also known
to their mutual benefit: Hejaz, Najd and parts of as Saudi Vision 2030, to reduce Saudi Arabia’s
Eastern (Al-Ahsa) and Southern (‘Asir) Arabia. The dependence on oil, diversify the economy and
Kingdom constitutes 80% of the Arabian Peninsula develop public service sectors, such as education,
(the world’s largest peninsula), covering a land area infrastructure, health, recreation and tourism.
of approximately 2,150,000 km2. The population
of Saudi Arabia grew from 22.56 million in 2004 to Saudi Arabia is also called the Land of the Two Holy
an estimated 32.6 million in May 2017, of which Mosques, a reference to Al-Masjid al-Haram (in
37% are non-nationalized immigrants (https:// Mecca) and Al-Masjid an-Nabawi (in Medina), the
www.stats.gov.sa). However, the Saudi fertility rate two holiest places in Islam. Saudi Arabia follows
(total births per woman) has declined significantly Islamic law (Sharia) and the Quran. The Quran and
from 7.2 in 1960 to 2.6 in 2015 (http://www. the Sunnah (the traditions of Muhammad) are
worldbank.org). The official language of Saudi declared to be the country’s constitution.
Arabia is Arabic, though English is widely spoken

26
Genetics in Saudi Arabia Arabia (3), there are commonly encountered
genetic disorders in the Saudi population like
High rates of consanguinity and high incidence of thalassaemia, intellectual disability, congenital
population-specific autosomal recessive disorders glaucoma, Bardet–Biedl syndrome, Meckel–
are well-known observations in Saudi Arabia. Gruber syndrome, organic acidaemia, lysosomal
Specific, novel genes in the Saudi population and, storage disorders, retinal dystrophies, hearing loss
more importantly, the founder effect in specific and primary microcephaly.
tribes or regions that present common disease-
causing variants both demand the provision of Consanguinity, Tribal Unions and
medical services across the Kingdom. However, Founder Effects
medical genetic services in Saudi Arabia are
limited to large cities and tertiary hospitals,
mainly governmental institutions, with few Currently, an estimated one billion people
services in private hospitals and unclear insurance globally live in communities with a preference for
coverage. Therefore, in 2018, the Saudi Council of consanguineous marriage (4, 5), mostly in North
Cooperative Health Insurance (https://www.cchi. Africa, the Middle East and Asia, where intra-
gov.sa) issued a unified health insurance policy that familial unions collectively account for 20–50%
mandated coverage of genetic disorders related to of all marriages (6-8) . Saudi Arabia has one of
the highest rates of consanguinity among Arab

An Overview of Mendelian Disorders in Saudi Arabia

birth defects.
countries, with the overall rate estimated at 52–
Saudi Arabia follows Sharia or Islamic law, which 58% (9-11) and certain areas even reaching 80%
is derived from the religious precepts of Islam, (12). First-cousin marriages are the most frequent
particularly the Quran and the Hadith. Islamic in Saudi Arabia, accounting for 28–40% of all
law considers Muslims to be one community marriages (9-12). The role consanguinity plays in
and prescribes their practice from birth to death, the prevalence of genetic disorders, especially
including their diet, personal hygiene and daily autosomal recessive disorders, is well-established.
social life. In Islamic law, ethical considerations In two large, whole exome cohorts conducted in
in genetics include support for the discovery of Saudi Arabia, Alfares et al. 2017 and Monies et al.
disorders and providing of treatment: “every illness 2017 (13, 14) both reported high rates (97%) of
has a cure” and “taking proper care of one’s health autosomal recessive disorders with homozygous
is the right of the body”. Based on the practice of disease-causing variants. Based on the calculated
Prophet Muhammad (peace be upon him), treating allele frequency of disease-causing variants, the
and managing diseases will lead to strategies for estimated probability a first-cousin union has a
their prevention, ultimately improving the health child homozygous for disease-causing variants is
of the entire community. approximately 0.7% (15). However, considering
the high rate of consanguinity, the likelihood
In this regard, Saudi Arabia faces an enormously that both first cousin parents are carriers for the
high incidence of genetic disorders. Many diseases-causing variants is nearly 1 in 8 (allowing
attempts have been made to challenge the for 100% likelihood of being a carrier for at least
burden to the community of inherited disorders, one disease-causing recessive disease, and 1/8
for example by establishing premarital screening sharing of variants between first cousins), which
for haemoglobinopathies (1), expanding medical results in 1:32 risk of having an affected child
genetics services, sponsoring physicians and with an autosomal recessive disorder. Also, first-
scientists in the field of genetics, launching cousin unions lead to increased frequencies of
fellowship programs in clinical genetics and homozygosity even for autosomal-dominant traits
master’s degree programs in genetic counselling, (16), or to unveiling novel phenotypes of dominant
increasing awareness of inherited disorders disorders in homozygous occurrence of disease
through the media and launching the Saudi causing alleles. The impact of consanguineous
Human Genome Program (SHGP), which aims to unions on the incidence of some of the genetic
sequence 100,000 human genomes to conduct disorders in the Saudi population is further detailed
world-class, genomics-based biomedical research in the following sections.
on the Saudi population in order to provide a
better understanding of the landscape of genetic Consanguineous unions and the tribal structure
disorders in Saudi Arabia (2). Whilst around 60 of Saudi Arabia have impacted the incidence of
genetic disorders were first described in Saudi genetic diseases in the country. The maintenance

GENETIC DISORDERS IN THE ARAB WORLD KINGDOM OF SAUDI ARABIA 27

 of tribal lineage and intra-tribal marriages over p.(Val128Met). These individuals often have
many generations has retained and spread private cognitive impairment, microcephaly, epilepsy,
genetic variants specific to a geographic location or nonspecific brain abnormalities and dysmorphic
tribe. Many of these founder variants of different facial features. ADAT3-related intellectual
autosomal recessive disorders were identified disability is considered a recognizable cause of
in Saudi patients even before the expansion intellectual disability in Saudi Arabia (24, 25).
of advanced technology like next-generation Another commonly encountered disease-causing
sequencing, demonstrating the high allele variant, in the well-known gene C12ORF57 which
frequency of these variants in the population. causes Temtamy syndrome, a form of intellectual
Some of these founder variants are tribal-specific. disability characterized by ocular involvement,
For example, the c.559G>T p.(Gly187X) in SLC26A3, epilepsy and dysgenesis of the corpus callosum.
which appears to be an Arab founder pathogenic The founder variant occurs in the methionine
variant causing familial chloride diarrhoea, was ATG starting codon of the gene (c.1A>G: p.Met1?)
identified and reported in 1998 (17). In another (26) and completely abolishes gene translation.
example, the homozygous deletion of 12 bp c.155- This variant alone represented around 1.5% of
166del p.(Ser52_Gly55del) in exon 3 of the TBCE all positive cases in one of the large cohorts of
gene was identified and reported in 2002, in both Saudi individuals, unselected for phenotype, who
Saudi and Kuwaiti patients, with Sanjad–Sakati underwent whole exome sequencing (13). Among
syndrome present with hypoparathyroidism, disorders in Saudi Arabia with the autosomal
retardation and delay of growth and development recessive mode of inheritance, over one-third
(18, 19). Moreover, the well-known splice are estimated to result from founder mutations,
junction variant in the Arabic population in CA2 with the remainder being private and limited to
(c.297+1G>A), which is located at the 5′ end of the family in which the variant was identified.
intron 2 and causes carbonic anhydrase type II The estimated percentage of disease-causing
deficiency leading to osteopetrosis autosomal founder variants in the Saudi population is 42%
recessive type 3, was initially reported in 1992 (Figure 1) (13). Disease-causing founder variants,
(20, 21). The c.436delC p.(Ala147Hisfs*9) in as yet unreported, are currently being discovered
DCAF17 was reported in 2008 from patients with in many genetics clinics as well as local and
Woodhouse–Sakati syndrome, who present with international diagnostic/research laboratories.
hypogonadism, alopecia, diabetes mellitus, mental Reporting founder variants greatly benefits, not
3 retardation, and extrapyramidal signs (22). Other only the family, but also often the whole tribe. For
common disorders with founder variants include example, the highest calculated carrier frequency
hereditary haemoglobin disorder B-thalassaemia for a single disease-causing variant in the Saudi
and sickle cell disease, particularly in provinces population, 0.015, is that of a founder variant in
with high rates of intermarriage and tribal unions. CYP1B1 NM_000104.3 c.182G>A p.(Gly61Glu),
Furthermore, the high incidence of rare genetic which causes congenital glaucoma (15). Knowing
and metabolic disorders in certain tribes have this information will improve management and
become clinical markers during the diagnostic and treatment, in addition to genetic counselling and
clinical evaluation of patients and individuals from prevention. Aside from single gene disorders,
those tribes. The combination of tribal societal many studies have reported that polygenic and
structure, high rates of consanguinity and large multifactorial disorders are also very common in
family size have elevated the prevalence of specific Saudi Arabia, attributing this to the high rates of
autosomal recessive diseases to alarming levels consanguinity. For example, there is a high incidence
in Saudi Arabia. For instance, some metabolic of congenital heart disease across the country,
disorders in Saudi Arabia like maple syrup urine increased rate of gastrointestinal tract anomalies
disease, very-long-chain fatty acid deficiency and in the Asir region, and in Najran regions there is
propionic acidaemia are almost entirely limited to a significantly high prevalence of hypothyroidism
specific tribes, with prevalence rates five to ten and hyperthyroidism (27). However, due to lack of
times higher than those worldwide (23). national registries of complex disorders, lifestyle
influence and phenocopies, as well as limited
Other non-metabolic founder variants are also robust epidemiological statistical studies on large
common in Saudi Arabia. The well-known ADAT3- cohorts, the impact of consanguinity on the
related intellectual disability has been described incidence of complex disorders is controversial.
in many individuals from Saudi families with For example, DNASE1L3 is linked to an autosomal
the homozygous founder variant c.382G>A recessive form of systemic lupus erythematosus

28
(SLE) which is considered as a multifactorial Dual diagnosis occurred in 3.3–6% of cases, with
complex autoimmune disease (28), and LRPAP1 diagnosis established by molecular testing. This
was found to be associated with severe myopia is similar to the published rate internationally
(29). GNB5, LRBA and TBXT are linked to mendelian and perhaps surprisingly less than expected,
forms of neuropsychiatric disorder, inflammatory considering the high rate of consanguinity (13, 14).
bowel disease with combined immunodeficiency
and neural tube defects, respectively (30-32). Novel Gene Discoveries
Advances in molecular genetic testing in recent
years made it possible to uncover, with reasonable
time and cost, many genetic disorders in which
consanguinity and a homozygous variant
predispose to autosomal recessive diseases. Novel
discovery of disease-causing genes in Saudi Arabia
has been tremendously improved by the ability
to analyse the entire set of autozygous intervals
(the autozygome) in consanguineous patients
(33), primarily focused on identifying homozygous

An Overview of Mendelian Disorders in Saudi Arabia

variants in autosomal recessive disorders. This
Figure 1: Representation of the distribution of disease- approach has helped increase the yield of
causing founder variants and private variants. molecular testing to identify novel candidate
genes not previously associated with diseases.
Zygosity and Mode of Inheritance The following sections discuss many of these novel
genes in further detail.
Previous reports have shown that, as expected,
most disease-causing variants in the Saudi
population are homozygous. Around 81% of all
Commonly Encountered Genetic
reported monogenic disorders in Saudi Arabia Disorders
are autosomal recessive, and of these recessive
disorders, 97% are homozygous, which is Inborn error of metabolism (IEM) is one of the
consistent with the high rate of consanguineous most common disorders in Saudi Arabia, with
unions in the Saudi population. Compound estimated incidence of 1:591 for all IEM including
heterozygous variants account for 5% of disease- small and large molecule subtypes (34) and 1:1043
causing variants. Non-recessive disorders in Saudi for all disorders included in newborn screening.
Arabia are less prevalent, accounting for 10–27% Propionic acidaemia has the highest incidence rate,
of autosomal dominant disorders and only 2–5% at 1:14,000, of all specific IEM disorders in Saudi
for X-linked disorders (Figure 2) (13, 14). Arabia (35). However, non-metabolic disorders
are also very common; Table 1 lists all commonly
observed genes and variants linked to disorders in
descending frequency.

As many clinical geneticists have observed,

there can be wide differences in the type and
prevalence of genetic diseases in Saudi Arabia
in comparison with the rest of the world. For
example, whilst phenylalanine hydroxylase
deficiency is by far the most common form of
phenylketonuria in the Caucasian population, the
6-pyruvoyl tetrahydrobiopterin synthase (PTPS)
deficiency is fairly common in Saudi Arabia (36)
due to a PTPS founder variant in one large tribe
in the country. Another disorder that is common
due to high carrier frequency is biotin-responsive
Figure 2: Distribution of genetic disorders in Saudi encephalopathy, which was mapped to SLC19A3 in
Arabia by mode of inheritance and allele state; AR: Saudi families (37). Among other “rare variants,” are
autosomal recessive, AD: autosomal dominant.

GENETIC DISORDERS IN THE ARAB WORLD KINGDOM OF SAUDI ARABIA 29

 Table 1: List of most common disease-causing variants and corresponding genes in Saudi population.

GENE VARIANTS
HBB c.20A>T:p.E7V and c.118C>T:p.Q40X

ABCA4 c.1633_1634insGAAA:p.N545fs

ABCC2 c.2273G>T:p.G758V

ACADM c.254C>T:p.T85I and c.362C>T:p.T121I and c.374C>T:p.T125I and c.104C>T:p.T35I and c.461C>T:p.T154I

ACADVL c.65C>A:p.S22X and c.203C>A:p.S68 and c.134C>A:p.S45X

ADAT3 c.430G>A:p.V144M

AGPAT2 c.335delC:p.P112fs

ALG3 c.344G>A:p.R115Q and c.188G>A:p.R63Q and c.512G>A:p.R171Q and c.407G>A:p.R136Q and c.368G>A:p.
R123Q

ALG8 c.104C>T:p.T35I

ANTXR2 c.134T>C:p.L45P and c.134T>C:p.L45P

ASNS c.962G>A:p.R321H and c.62G>A:p.R321H and c.1148G>A:p.R383H

ATP7B c.46T>C:p.S16P and c.1556T>C:p.F519S and c.2230T>C:p.S744P and c.2230T>C:p.S744P and c.1897T>C:p.
S633P

ATP8B1 c.1594G>A:p.A532T

C12ORF57 c.1A>G:p.M1V

CANT1 c.906_907insGCGCC:p.S303fs

CC2D2A c.2936delG:p.R979fs and c.3083delG:p.R1028fs

CFTR c.416A>T:p.H139L

3 CFTR c.1911delG:p.Q637fs and c.129delG:p.Q43fs

CFTR c.3700A>G:p.I1234V and c.1918A>G:p.I640V

CRYBB1 c.171delG:p.G57fs

CTSC c.815G>C:p.R272P and c.371G>C:p.R124P

CYP1B1 c.182G>A:p.G61E

CYP1B1 c.1405C>T:p.R469W

CYP21A2 c.760A>G:p.M254V and c.850A>G:p.M284V

CYP2U1 c.947A>T:p.D316V and c.320A>T:p.D107V

DBT c.360delA:p.K120fs

DCAF17 c.436delC:p.L146fs and c.436delC:p.L146fs

DHCR7 c.1A>G:p.M1V

DPYD c.257C>T:p.P86L

DYNC2H1 c.6035C>T:p.A2012V

EPCAM c.499dupC:p.L166fs

FAM98C 844C>T:p.R282X

30
FKRP c.941C>T:p.T314M

FYCO1 c.449T>C:p.I150T

G6PD c.653C>T:p.S218F and c.563C>T:p.S188F

G6PD c.233T>C:p.I78T and c.143T>C:p.I48T

GEMIN4 c.2452T>C:p.W818R

GPR179 c.349G>A:p.D117N

GUSB c.991C>T:p.R331W and c.1429C>T:p.R477W

IRAK4 c.451delT:p.S151fs and c.823delT:p.S275fs

ISCA2 c.229G>A:p.G77S

KCNV2 c.427G>T:p.E143X

LAMC3 c.1931_1932insT:p.S644fs

An Overview of Mendelian Disorders in Saudi Arabia

MC4R c.485C>T:p.T162I

MYO18B c.854C>A:p.S285X and c.5444C>A:p.S1815X and c.4367C>A:p.S1456X and c.6548C>A:p.S2183X and

c.6551C>A:p.S2184X and c.6545C>A:p.S2182X and c.6905C>A:p.S2302X

NPHP4 c.673G>T:p.G225C

NR2E3 c.932G>A:p.R311Q

OTOF c.1565G>A:p.R522H and c.3305G>A:p.R1102H and and c.3074G>A:p.R1025H,OTOF and c.5375G>A:p.R1792H

PEX5 c.1467T>G:p.N489K and c.1554T>G:p.N518K and c.1578T>G:p.N526K and c.1623T>G:p.N541K and

c.1641T>G:p.N547K and c.1578T>G:p.N526K

PKHD1 c.4870C>T:p.R1624W

PLCE1 c.2134C>T:p.Q712X and c.3058C>T:p.Q1020X

RGS9BP c.330_342del:p.R110fs

RP1 c.606C>A:p.D202E

RP1L1 c.5959C>T:p.Q1987X

SLC26A3 c.559G>T:p.G187X and c.454G>T:p.G152X

SLC3A1 c.260T>A:p.M87K and c.566T>A:p.M189K and c.1400T>A:p.M467K

STXBP2 c.314C>T:p.P105L and c.1430C>T:p.P477L and c.1421C>T:p.P474L and c.1463C>T:p.P488L

TANGO2 c.94C>T:p.R32X and c.217C>T:p.R73X

TBCE c.151_162del:p.51_54del

TMEM231; c.223G>A:p.V75I and c.751G>A:p.V251I and c.316G>A:p.V106I and c.664G>A:p.V222I

CHST5

TULP1 c.742C>T:p.Q248X and c.901C>T:p.Q301X and c.898C>T:p.Q300X

TYR c.230G>A:p.R77Q

TYRP1 c.1557T>G:p.Y519X

WDR19 c.1568G>TA44:C65:p.S523I and c.2297G>T:p.S766I and c.2777G>T:p.S926I

GENETIC DISORDERS IN THE ARAB WORLD KINGDOM OF SAUDI ARABIA 31

 the transversion change c.722G>C p.Cys241Ser in
PSAP which appears to be relatively more common
in Saudi Arabia, causing sphingolipid activator
protein B deficiency (38) as w well as CLN6 gene
defects that lead to late infantile neuronal ceroid
lipofuscinosis (39). Table 2 lists the most common
metabolic disorders observed in Saudi population,
in descending order.

Table 2: Diseases listed by decreasing incidence of the common metabolic disorders in Saudi Arabia with the corresponding
OMIM number

Dubin-Johnson syndrome, 237500

Glycogen storage disease IIIa, 232400
Dihydropyrimidine dehydrogenase deficiency, 274270
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, 616277
Asparagine synthetase deficiency, 615574
Cystinuria, 220100
Wilson disease, 277900
VLCAD deficiency, 201475
Lipodystrophy, congenital generalized, type 1, 608594
Biotinidase deficiency, 253260
Cholestasis, benign recurrent intrahepatic, 243300
Acyl-CoA dehydrogenase, medium chain, deficiency of, 201450
Succinyl CoA:3-oxoacid CoA transferase deficiency, 245050
Congenital disorder of glycosylation, type Id, 601110

3 Congenital disorder of glycosylation, type Ih, 608104

Congenital disorder of glycosylation, type It, 614921
Smith-Lemli-Opitz syndrome, 270400
Propionic acidemia, 606054
Cholestasis, progressive familial intrahepatic 4, 615878
Multiple mitochondrial dysfunctions syndrome 4, 616370
3-Methylcrotonyl-CoA carboxylase 2 deficiency, 210210
Maple syrup urine disease, type II, 248600
Mucopolysaccharidosis Ih, 607014
Mucopolysaccharidosis VII, 253220
Peroxisome biogenesis disorder 2A (Zellweger), 214110
Gaucher disease, perinatal lethal, 608013
Niemann-Pick disease, type A, 257200
Crigler-Najjar syndrome, type I, 218800
Rhizomelic chondrodysplasia punctata, type 2, 222765
Combined oxidative phosphorylation deficiency 2, 610498
Myopathy due to myoadenylate deaminase deficiency, 615511
Chondrodysplasia punctata, X-linked recessive, 302950
Methylmalonic aciduria, mut(0) type, 251000
Hyperphenylalaninemia, non-PKU mild, 261600
Dihydrolipoamide dehydrogenase deficiency, 246900
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, 611105

32
 Skeletal Dysplasia in Saudi Arabia Microphthalmia

Most reported skeletal dysplasia disorders in Saudi Regarding microphthalmia, or birth defects that
Arabia are autosomal recessive. Their calculated lead to anatomic malformations of the eye,
incidence based on the carrier allele frequency is testing multiple affected Saudi patients led to
1:397. Osteogenesis imperfecta (OI) is the most the discovery of a landscape of genetic causes in
common skeletal dysplasia in Saudi Arabia (16%). the Saudi population, mainly associated with the
Whilst OI is known to be an autosomal dominant posterior type. The reported causative genes for
disorder, autosomal recessive OI accounts for 64% microphthalmia in the Saudi population are, in
of OI cases in Saudi Arabia, compared to the rest descending order of frequency: PRSS56 (24%),
of the world, where 85% of cases are de novo C12orf57, ALDH1A3 and MFRP (11%), RAB3GAP1
disease-causing variants in collagen genes (40). (6%), OTX2, PXDN and STRA6 (4%) and other
Also, novel genes have been described in the Saudi genetic causes (24%) which occur at least in one
population, which include WNT3A, PAN2, RIN1 and single family (43).
DIP2C. Figure 3 shows the percentage of disorders
classified as skeletal dysplasia identified in Saudi Cholestatic Liver Disease
Arabia (41).
Progressive, familial intrahepatic cholestasis (PFIC)

An Overview of Mendelian Disorders in Saudi Arabia

is the most common form of familial liver disorder
in the Saudi population. Two genes are responsible
for nearly half of all cases of PFIC: ABCB11,
which causes PFIC2 (14, 44), and ABCB4, which
causes PFIC3. Several other genes are linked to
cholestatic liver diseases in the Saudi population,
including TJP2, which typically causes familial
hypercholanaemia and has rarely been reported
to cause cholestatic liver disease; UGT1A1, which
causes hereditary hyperbilirubinemias, and ATP7B,
which causes Wilson’s disease. The estimated
Osteogenesis imperfecta Polydactyly-Syndactyly-Triphalangism carrier frequency of all cholestatic liver disease–
group
Ciliopathies with skeletal involvement causing variants in Saudi Arabia is 1:87, which
Spondyloepimetaphyseal dysplasia Lysosomal storage disorders
Not Classified Slender bone dysplasia group
translates to a minimum incidence of 1:7246 (44).

Figure 3: The percentage of skeletal dysplasia disorders Retinal Dystrophies

identified in Saudi Arabia based on the International
Skeletal Dysplasia Nosology classification. The many causes of retinal dystrophies (RD)
can be classified into syndromic and isolated, or
non-syndromic. The major causes of RD in the
Neurogenetic Genes in Saudi Arabia Saudi population are isolated, non-syndromic
retinitis pigmentosa (RP). In descending order of
Neurological disorders account for the largest prevalence, the causative genes are: ABCA4, which
category of Mendelian disorders in humans. causes Stargardt’s disease 1 or juvenile macular
Applying whole exome sequencing to patients degeneration; TULP1, which leads to retinitis
with neurogenetic disorders from multiple pigmentosa 14; MERTK, which causes retinitis
consanguineous families and looking at regions pigmentosa 38; CRB1, which causes retinitis
of homozygosity using this approach lead to the pigmentosa 12; RPE65, which causes retinitis
discovery of 36 associated genes in the Saudi pigmentosa 20; RPGRIP1, which causes cone-
population that have not been previously reported rod dystrophy 13; IMPG2, which causes retinitis
(SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, pigmentosa 56; KCNV2, which causes retinal
CLHC1,–– C12orf4, WDR93, ST7, MATN4, SEC24D, cone dystrophy 3B; NR2E3, which causes retinitis
PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, pigmentosa 37 and RP1, which causes retinitis
KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, pigmentosa.
ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1,
NUP107, TMEM92, EPB41L4A and FAM120AOS,
DENND5A, NEMF and DNHD1) (41, 42).

GENETIC DISORDERS IN THE ARAB WORLD KINGDOM OF SAUDI ARABIA 33

 The most common causes of syndromic, non-
isolated RP in the Saudi population are ALMS1,
which leads to Alstrom syndrome, as well as BBS2
and BBS4, which lead to Bardet-Biedl syndromes 2
and 4, respectively. Other novel candidate genes
identified in the Saudi population as causing
RP include AGBL5, CDH16 and DNAJC17 (45).
Additionally, six novel candidate disease-causing Bardet Biedl Syndrome Meckel Syndrome
genes were identified (C21orf2, EMC1, KIAA1549, Joubert Syndrome Short-Rib Thoracic Dysplasia Others
GPR125 ACBD5 and DTHD1), two of which (ACBD5
and DTHD1) were observed in the context of Figure 4: Distribution of the aetiology of ciliopathies in
syndromic forms of RD described for the first time the Saudi population.
(46). accounting for 18% of all identified cases.
LONP1 causes cerebral, ocular, dental, auricular
Congenital Glaucoma and skeletal anomalies (CODAS), accounting
for 9% of identified cases. GEMIN4, linked to
CYP1B1 is the major cause of congenital glaucoma neurodevelopmental disorder with microcephaly,
in the Saudi population, with two disease-causing cataracts and renal abnormalities, accounts for
variants, c.182G>A;p.(Gly61Glu) and c.1405C>T ; 7%. Each single gene of CYP51A1, EPHA2, FYCO1,
p.(Arg469Trp), accounting for more than 86% of GCNT2, RIC1 and SIL1 accounts for around 4%
all identified cases (47). (Figure 5). Two genes were reported as novel
candidate genes for cataracts, TAF1A (cataract
Familial Congenital Hydrocephalus with global developmental delay) and WDR87
(non-syndromic cataract), along with a founder
Whilst the most common cause of familial variant in RIC1 c.3794G>C p.(Arg1265Pro), that
congenital hydrocephalus worldwide is the causes global developmental delay, microcephaly
X-linked L1CAM, this gene is not commonly and brain atrophy with or without cleft lip and
encountered in the Saudi population, perhaps palate (50).
due to overrepresentation of autosomal recessive
disorders. Two genes account for most cases of
3 familial congenital hydrocephalus in the Saudi
population: POMT1, which causes muscular
dystrophy-dystroglycanopathy normally present
with significant elevation in serum creatine kinase,
and MPDZ, which causes non-syndromic autosomal
recessive hydrocephalus 2 (48). Furthermore,
ciliopathies account for a considerable part of
congenital hydrocephalus.

Ciliopathies
CRYBB1 LONP1 GEMIN4 CYP51A1
EPHA2 FYCO1 GCNT2 RIC1 SIL1
Some ciliopathies in the Saudi population are Not Classified
secondary to Bardet-Biedl syndromes, which
Figure 5: Distribution of the most common genes
account for around 30% of cases, followed by
causing cataracts in the Saudi population.
Meckel syndrome, which accounts for 24%, Joubert
syndrome, which accounts for 17%, and short-rib Microcephaly
thoracic dysplasia, which accounts for 7% of cases.
Several genes, reported as novel candidate genes Microcephaly primary hereditary (MCPH) or
in the Saudi population, are shown in Figure 4 (49). autosomal recessive primary microcephaly
is another common disorder in Saudi Arabia.
Disease-causing variants were encountered in
Cataract 10 genes (MCPH1, WDR62, CDK5RAP2, ASPM,
STIL, CEP135, CEP152, CENPJ, CIT, MFSD2A) out
Cataracts are divided into syndromic or isolated of around 18 genes which are known to cause
forms. CRYBB1 is the leading cause of autosomal MCPH. These variants account for 24% of all cases
recessive type 3 cataract 17 in the Saudi population,

34
with microcephaly in Saudi population. Apart goals of genetics. Any treatment or procedure
from these known MCPH genes, other genes that could harm the foetus or mother should be
with established phenotypes (60%) and novel avoided. The goals of prevention are to lower
or candidate genes (16%) have also been shown the incidence of genetic disorders, prevent the
to cause microcephaly in the Saudi population burdens of a chronic illness on families and the
(Alkuraya, unpublished data). community, and minimize the economic impact
of genetic disorders, which can be highly costly
Prenatal Genetics and Prevention in terms of management and treatment. Genetic
disorders can be prevented in many ways. For
Genetics example, Saudi Arabia implemented premarital
screening for haemoglobinopathies (thalassaemia
Prenatal genetic testing in Saudi Arabia is
and sickle cell disease) which is mandatory to
constrained by ethical and cultural beliefs, in
perform. However, the decision to act based on its
addition to Islamic law. Although many prenatal
outcome is left for the couple to make. Also, carrier
services are available across the country,
testing for well-known familial variants is available
the clinical utility and the impact of prenatal
at many governmental or private laboratories.
diagnostic modality is inadequate either due to
Recently, some laboratories and hospitals have
limited availability of prenatal testing around the
started offering whole exome sequencing as a
country or to extended turnaround time to obtain

An Overview of Mendelian Disorders in Saudi Arabia

method to test for the carrier status of any lethal
the diagnostics results. However, recent years
or chronic genetic disorder, meant primarily for
have seen growth in chorionic villus sampling and
consanguineous couples. Genetic counselling
amniocentesis, as well as non-invasive prenatal
services are in very short supply in Saudi Arabia
screening (NIPS or NIPT).
considering the population size. One paper
estimating the impact of premarital screening on
Pre-implantation Genetic Diagnostic (PGD) services
the incidence of the two haemoglobinopathies
in Saudi Arabia are not available today except in
demonstrated a reduction in thalassaemia, but no
few governmental and private centres. Normally,
change in the incidence of sickle cell disease (1).
such services are performed primarily for carriers
of chromosomal structural changes, such as
translocations, or those of monogenic diseases. Ethical Considerations
Even though PGD offers efficient and precise
results for such cases there are still many social, Saudi Arabia follows Islamic law. Fatwa number
financial and cultural limitations in Saudi Arabia. 4 of the Islamic Fiqh council of the Islamic World
Around 45% of couples opt for early prenatal League, Makkah Al Mukaramah, at its 12th session
diagnosis, compared to 35% who choose PGD (33). (Makkah, 10–17 February 1990) contemplates
PGD provides an ideal solution to the challenge of the option of abortion under certain, specific
terminating a pregnancy, which is constrained by conditions. Islamic bioethics emphasizes the
Islamic law. importance of preventing illness, and any measure
to prevent mental handicap in children is highly
NIPS is also available in the country; however, recommended by Islamic jurists (52). The fatwa
there are no clear guidelines available regarding determined that an abortion may take place only
whom to test and what to test for. if a committee of three specialized, competent
physicians has decided the foetus is grossly
Congenital and genetic disorders are responsible malformed and that its life would be a calamity for
for a major proportion of infant mortality, morbidity both the family and itself. The malformation must
and disability in Arab countries (51). Public health be untreatable, unmanageable and very serious,
measures, albeit insufficient, are directed at the and the abortion may only be performed prior to
prevention of congenital and genetic disorders, the 120th day after conception (computed from
and are coupled with inadequate health care the date of fertilization, not the last menstrual
before and during pregnancy. Services for the cycle) (52). Beyond 120 days, considered to be
prevention and control of genetic disorders are after ensoulment, abortion is only allowed if there
restricted by certain cultural, legal and religious is a danger threatening the mother’s life, not
limitations. All of this leads to the high incidence her health. On the basis of this fatwa, abortions
of physically disabled children in Arab countries. of foetuses with serious congenital diseases are
Since most genetic disorders have no treatment performed in Saudi hospitals.
yet, preventing severe outcomes is one of the main

GENETIC DISORDERS IN THE ARAB WORLD KINGDOM OF SAUDI ARABIA 35

 Adoption is not acceptable in Islamic law, though Qurachi MM, Al-Omar AA. Regional variations in
fostering children is allowed; the lineage of the child the prevalence of consanguinity in Saudi Arabia.
must persist to his or her natural parents. Advances Saudi Med J. 2007;28(12):1881-4.
in feto-maternal medicine and in vitro fertilization 13. Monies D, Abouelhoda M, AlSayed M, Alhassnan
Z, Alotaibi M, Kayyali H, et al. The landscape of
have led to new applications, like sperm, ovum or
genetic diseases in Saudi Arabia based on the first
pre-embryo donation and other interventions. All 1000 diagnostic panels and exomes. Hum Genet.
of these practices are unacceptable in the view 2017;136(8):921-39.
of Islamic teachings, which recognize procreation 14. Alfares A, Alfadhel M, Wani T, Alsahli S, Alluhaydan
only within the bounds of husband and wife I, Al Mutairi F, et al. A multicenter clinical exome
and exclude any third party from the process. study in unselected cohorts from a consanguineous
Furthermore, no procreation is allowed after the population of Saudi Arabia demonstrated a high
death of a spouse or in the event of a divorce. diagnostic yield. Mol Genet Metab. 2017;121(2):91-
5.
15. Abouelhoda M, Sobahy T, El-Kalioby M, Patel
References N, Shamseldin H, Monies D, et al. Clinical
genomics can facilitate countrywide estimation of
1. Memish ZA, Saeedi MY. Six-year outcome of autosomal recessive disease burden. Genet Med.
the national premarital screening and genetic 2016;18(12):1244-9.
counseling program for sickle cell disease and 16. Teebi AS, Teebi SA. Genetic diversity among the
beta-thalassaemia in Saudi Arabia. Ann Saudi Med. Arabs. Community Genet. 2005;8(1):21-6.
2011;31(3):229-35. 17. Hoglund P, Auranen M, Socha J, Popinska K, Nazer H,
2. Project Team SG. The Saudi Human Genome Rajaram U, et al. Genetic background of congenital
Program: An oasis in the desert of Arab medicine chloride diarrhea in high-incidence populations:
is providing clues to genetic disease. IEEE Pulse. Finland, Poland, and Saudi Arabia and Kuwait. Am J
2015;6(6):22-6. Hum Genet. 1998;63(3):760-8.
3. Alkuraya FS. Genetics and genomic medicine 18. Parvari R, Hershkovitz E, Grossman N, Gorodischer
in Saudi Arabia. Mol Genet Genomic Med. R, Loeys B, Zecic A, et al. Mutation of TBCE causes
2014;2(5):369-78. hypoparathyroidism-retardation-dysmorphism and
4. Bittles AH, Black ML. Evolution in health and autosomal recessive Kenny-Caffey syndrome. Nat
medicine Sackler colloquium: Consanguinity, Genet. 2002;32(3):448-52.
human evolution, and complex diseases. Proc Natl 19. Naguib KK, Gouda SA, Elshafey A, Mohammed F,
Acad Sci U S A. 2010;107 Suppl 1:1779-86. Bastaki L, Azab AS, et al. Sanjad-Sakati syndrome/
3 Kenny-Caffey syndrome type 1: a study of 21 cases
5. Modell B, Darr A. Science and society: genetic
counselling and customary consanguineous in Kuwait. East Mediterr Health J. 2009;15(2):345-
marriage. Nat Rev Genet. 2002;3(3):225-9. 52.
6. Hamamy H. Consanguineous marriages : 20. Hu PY, Roth DE, Skaggs LA, Venta PJ, Tashian RE,
Preconception consultation in primary health care Guibaud P, et al. A splice junction mutation in
settings. J Community Genet. 2012;3(3):185-92. intron 2 of the carbonic anhydrase II gene of
7. Tadmouri GO, Nair P, Obeid T, Al Ali MT, Al Khaja osteopetrosis patients from Arabic countries. Hum
N, Hamamy HA. Consanguinity and reproductive Mutat. 1992;1(4):288-92.
health among Arabs. Reprod Health. 2009;6:17. 21. Bosley TM, Salih MA, Alorainy IA, Islam MZ,
8. 8. Hamamy H, Antonarakis SE, Cavalli-Sforza LL, Oystreck DT, Suliman OS, et al. The neurology of
Temtamy S, Romeo G, Kate LP, et al. Consanguineous carbonic anhydrase type II deficiency syndrome.
marriages, pearls and perils: Geneva International Brain. 2011;134(Pt 12):3502-15.
Consanguinity Workshop Report. Genet Med. 22. Alazami AM, Al-Saif A, Al-Semari A, Bohlega S,
2011;13(9):841-7. Zlitni S, Alzahrani F, et al. Mutations in C2orf37,
9. Al-Abdulkareem AA, Ballal SG. Consanguineous encoding a nucleolar protein, cause hypogonadism,
marriage in an urban area of Saudi Arabia: rates alopecia, diabetes mellitus, mental retardation,
and adverse health effects on the offspring. J and extrapyramidal syndrome. Am J Hum Genet.
Community Health. 1998;23(1):75-83. 2008;83(6):684-91.
10. Al-Owain M, Al-Zaidan H, Al-Hassnan Z. Map of 23. Zayed H. Propionic acidemia in the Arab World.
autosomal recessive genetic disorders in Saudi Gene. 2015;564(2):119-24.
Arabia: concepts and future directions. Am J Med 24. Alazami AM, Hijazi H, Al-Dosari MS, Shaheen R,
Genet A. 2012;158A(10):2629-40. Hashem A, Aldahmesh MA, et al. Mutation in
11. El-Hazmi MA, al-Swailem AR, Warsy AS, al-Swailem ADAT3, encoding adenosine deaminase acting on
AM, Sulaimani R, al-Meshari AA. Consanguinity transfer RNA, causes intellectual disability and
among the Saudi Arabian population. J Med Genet. strabismus. J Med Genet. 2013;50(7):425-30.
1995;32(8):623-6. 25. El-Hattab AW, Saleh MA, Hashem A, Al-Owain M,
12. El-Mouzan MI, Al-Salloum AA, Al-Herbish AS, Asmari AA, Rabei H, et al. ADAT3-related intellectual
disability: Further delineation of the phenotype.

36
 Am J Med Genet A. 2016;170A(5):1142-7. 38. Al-Hassnan ZN, Al Dhalaan H, Patay Z, Faqeih E,
26. Alrakaf L, Al-Owain MA, Busehail M, Alotaibi MA, Al-Owain M, Al-Duraihem A, et al. Sphingolipid
Monies D, Aldhalaan HM, et al. Further delineation activator protein B deficiency: report of 9 Saudi
of Temtamy syndrome of corpus callosum patients and review of the literature. J Child Neurol.
and ocular abnormalities. Am J Med Genet A. 2009;24(12):1513-9.
2018;176(3):715-21. 39. Al-Muhaizea MA, Al-Hassnan ZN, Chedrawi A.
27. Abu-Elmagd M, Assidi M, Schulten HJ, Dallol A, Variant late infantile neuronal ceroid lipofuscinosis
Pushparaj P, Ahmed F, et al. Individualized medicine (CLN6 gene) in Saudi Arabia. Pediatr Neurol.
enabled by genomics in Saudi Arabia. BMC Med 2009;41(1):74-6.
Genomics. 2015;8 Suppl 1:S3. 40. Marini JC, Forlino A, Bachinger HP, Bishop NJ, Byers
28. Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, PH, Paepe A, et al. Osteogenesis imperfecta. Nat
Almurshedi F, Alhashmi N, et al. Loss-of-function Rev Dis Primers. 2017;3:17052.
variant in DNASE1L3 causes a familial form 41. Maddirevula S, Alsahli S, Alhabeeb L, Patel N,
of systemic lupus erythematosus. Nat Genet. Alzahrani F, Shamseldin HE, et al. Expanding the
2011;43(12):1186-8. phenome and variome of skeletal dysplasia. Genet
29. Aldahmesh MA, Khan AO, Alkuraya H, Adly N, Med. 2018.
Anazi S, Al-Saleh AA, et al. Mutations in LRPAP1 42. Anazi S, Maddirevula S, Faqeih E, Alsedairy H,
are associated with severe myopia in humans. Am J Alzahrani F, Shamseldin HE, et al. Clinical genomics
Hum Genet. 2013;93(2):313-20. expands the morbid genome of intellectual
30. Shamseldin HE, Masuho I, Alenizi A, Alyamani S, disability and offers a high diagnostic yield. Mol

An Overview of Mendelian Disorders in Saudi Arabia

Patil DN, Ibrahim N, et al. GNB5 mutation causes a Psychiatry. 2017;22(4):615-24.
novel neuropsychiatric disorder featuring attention 43. Patel N, Khan AO, Alsahli S, Abdel-Salam G, Nowilaty
deficit hyperactivity disorder, severely impaired SR, Mansour AM, et al. Genetic investigation of
language development and normal cognition. 93 families with microphthalmia or posterior
Genome Biol. 2016;17(1):195. microphthalmos. Clin Genet. 2018;93(6):1210-22.
31. Alangari A, Alsultan A, Adly N, Massaad MJ, Kiani IS, 44. Shagrani M, Burkholder J, Broering D, Abouelhoda
Aljebreen A, et al. LPS-responsive beige-like anchor M, Faquih T, El-Kalioby M, et al. Genetic profiling
(LRBA) gene mutation in a family with inflammatory of children with advanced cholestatic liver disease.
bowel disease and combined immunodeficiency. J Clin Genet. 2017;92(1):52-61.
Allergy Clin Immunol. 2012;130(2):481-8 e2. 45. Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif
32. Shaheen R, Alshail E, Alaqeel A, Ansari S, Hindieh F, H, Khan AO, et al. Expanding the clinical, allelic, and
Alkuraya FS. T (brachyury) is linked to a Mendelian locus heterogeneity of retinal dystrophies. Genet
form of neural tube defects in humans. Hum Genet. Med. 2016;18(6):554-62.
2015;134(10):1139-41. 46. Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan
33. Alkuraya FS. Impact of new genomic tools on the AO, Al-Owain M, et al. Autozygome-guided exome
practice of clinical genetics in consanguineous sequencing in retinal dystrophy patients reveals
populations: the Saudi experience. Clin Genet. pathogenetic mutations and novel candidate
2013;84(3):203-8. disease genes. Genome Res. 2013;23(2):236-47.
34. Alfadhel M, Benmeakel M, Hossain MA, Al Mutairi 47. Alsaif HS, Khan AO, Patel N, Alkuraya H, Hashem
F, Al Othaim A, Alfares AA, et al. Thirteen year M, Abdulwahab F, et al. Congenital glaucoma and
retrospective review of the spectrum of inborn CYP1B1: an old story revisited. Hum Genet. 2018.
errors of metabolism presenting in a tertiary 48. 48. Shaheen R, Sebai MA, Patel N, Ewida N, Kurdi
center in Saudi Arabia. Orphanet J Rare Dis. W, Altweijri I, et al. The genetic landscape of
2016;11(1):126. familial congenital hydrocephalus. Ann Neurol.
35. Alfadhel M, Al Othaim A, Al Saif S, Al Mutairi F, 2017;81(6):890-7.
Alsayed M, Rahbeeni Z, et al. Expanded Newborn 49. Shaheen R, Szymanska K, Basu B, Patel N, Ewida N,
Screening Program in Saudi Arabia: Incidence Faqeih E, et al. Characterizing the morbid genome
of screened disorders. J Paediatr Child Health. of ciliopathies. Genome Biol. 2016;17(1):242.
2017;53(6):585-91. 50. Patel N, Anand D, Monies D, Maddirevula S, Khan
36. Al Aqeel A, Ozand PT, Gascon G, Nester M, al AO, Algoufi T, et al. Novel phenotypes and loci
Nasser M, Brismar J, et al. Biopterin-dependent identified through clinical genomics approaches to
hyperphenylalaninemia due to deficiency of pediatric cataract. Hum Genet. 2017;136(2):205-
6-pyruvoyl tetrahydropterin synthase. Neurology. 25.
1991;41(5):730-7. 51. Al-Gazali L, Hamamy H, Al-Arrayad S.
37. Zeng WQ, Al-Yamani E, Acierno JS, Jr., Slaugenhaupt Genetic disorders in the Arab world. BMJ.
S, Gillis T, MacDonald ME, et al. Biotin-responsive 2006;333(7573):831-4.
basal ganglia disease maps to 2q36.3 and is 52. Al-Aqeel AI. Ethical guidelines in genetics and
due to mutations in SLC19A3. Am J Hum Genet. genomics. An Islamic perspective. Saudi Med J.
2005;77(1):16-26. 2005;26(12):1862-70.

GENETIC DISORDERS IN THE ARAB WORLD KINGDOM OF SAUDI ARABIA 37