Autosomal recessive disorders: Autosomal recessive disorders: the Middle East perspectivethe Middle East perspective

Lihadh Al-GazaliLihadh Al-GazaliFaculty of Medicine and Health Faculty of Medicine and Health

SciencesSciencesUAE UniversityUAE University

DEFINITION OF THE MIDDLE EAST

Lancet Vol 367, 2006

UNITED ARAB EMIRATES

Burj Al Arab in DubaiBurj Al Arab in Dubai

Faculty of Medicine and Health Sciences United Arab Emirates

University

Characteristics of the population in the Characteristics of the population in the Middle EastMiddle East

Multi-ethnic & diverseMulti-ethnic & diverse Presence of isolated communities, Presence of isolated communities,

like Bedouins, Druze, Nubianslike Bedouins, Druze, Nubians High mobilityHigh mobility Large family sizeLarge family size High level of consanguinityHigh level of consanguinity

Consanguinity Rates and Inbreeding Coefficients Consanguinity Rates and Inbreeding Coefficients in the Middle Eastin the Middle East

CountryCountryConsanguinityConsanguinityAverage Inbreeding Average Inbreeding CoefficientCoefficient

BahrainBahrain31.8 – 44.531.8 – 44.50.0152 – 0.01660.0152 – 0.0166

EgyptEgypt29290.01010.0101

IraqIraq46.446.40.02250.0225

Israeli ArabsIsraeli Arabs20.6 – 52.920.6 – 52.90.00993 – 0.02530.00993 – 0.0253

JordanJordan25.6 – 52.125.6 – 52.10.0142 – 0.02840.0142 – 0.0284

KuwaitKuwait54.354.30.02190.0219

LebanonLebanon16.5 – 29.616.5 – 29.60.00880.0088

OmanOman35.935.90.01980.0198

QatarQatar54540.027060.02706

Saudi ArabiaSaudi Arabia41.4 – 51.741.4 – 51.70.0196 – 0.03120.0196 – 0.0312

UAEUAE50.550.50.02220.0222

YemenYemen40 – 44.740 – 44.70.0212 – 0.24420.0212 – 0.2442

Autosomal Recessive disorders in ArabsAutosomal Recessive disorders in ArabsThe The CCatalogue for atalogue for TTransmission ransmission GGenetics in enetics in AArabs (CTGA)rabs (CTGA)

Number of genetic disorders in Arabs - 806Number of genetic disorders in Arabs - 806 Autosomal disorders - 701Autosomal disorders - 701

AR -513AR -513

AD -206AD -206 X-Linked disorders - 47X-Linked disorders - 47

XR -23XR -23

XD -10XD -10

www.cags.org.ae

Autosomal Recessive (AR) Disorders in Autosomal Recessive (AR) Disorders in the Middle Eastthe Middle East

Common AR disordersCommon AR disorders Relatively common AR disordersRelatively common AR disorders AR disorders that cluster in certain AR disorders that cluster in certain

communitiescommunities AR disorders which are limited to 1 or AR disorders which are limited to 1 or

2 extended families2 extended families New AR disordersNew AR disorders

Rates of common single gene disorders in Arab Countries

Up to 27% of males have

G6PD deficiency

Up to 27% of males have

G6PD deficiency

Sickle cell carrier rateUp to 25%

Sickle cell carrier rateUp to 25%

? Deaf-mutism? Congenital adrenal

hyperplasia

? Deaf-mutism? Congenital adrenal

hyperplasia

Alpha thalassemia carrier rateUp to 49%

Alpha thalassemia carrier rateUp to 49%

Familial Mediterranean Fever carrier rate

Up to 18%

Familial Mediterranean Fever carrier rate

Up to 18%

Beta thalassemia carrier rate Up to 15%

Beta thalassemia carrier rate Up to 15%

Common single gene disorders in

Arab countries

Common single gene disorders in

Arab countries

Up to 27% of males have

G6PD deficiency

Up to 27% of males have

G6PD deficiency

Sickle cell carrier rateUp to 25%

Sickle cell carrier rateUp to 25%

? Deaf-mutism? Congenital adrenal

hyperplasia

? Deaf-mutism? Congenital adrenal

hyperplasia

Alpha thalassemia carrier rateUp to 49%

Alpha thalassemia carrier rateUp to 49%

Familial Mediterranean Fever carrier rate

Up to 18%

Familial Mediterranean Fever carrier rate

Up to 18%

Beta thalassemia carrier rate Up to 15%

Beta thalassemia carrier rate Up to 15%

Common single gene disorders in

Arab countries

Common single gene disorders in

Arab countries

Prevalence of Haemoglobinopathies Prevalence of Haemoglobinopathies in the Middle Eastin the Middle East

CountryCountrythal carrierthal carrierthal carrierthal carrierSickle Cell Sickle Cell TraitTrait

BahrainBahrain2.92.924.224.2 13.813.8

EgyptEgypt4.54.5NANA NANA

IraqIraq4.64.6NANA 6.5 – 166.5 – 16

JordanJordan3 – 5.93 – 5.92 – 3.52 – 3.5 0.5 – 60.5 – 6

KuwaitKuwaitNANA5 – 105 – 10 NANA

LebanonLebanon22NANA 0.30.3

OmanOman2.2 – 42.2 – 4NANA 5.8 – 105.8 – 10

Saudi Saudi ArabiaArabia

1 – 151 – 155 – 105 – 10 1 – 251 – 25

UAEUAE8.38.34949 1.41.4

Common Genetic Disorders in the Common Genetic Disorders in the UAEUAE

Thalassaemia Thalassaemia

Major health problem in UAEMajor health problem in UAE Mutation analysis: Mutation analysis:

UAE is the most heterogeneousUAE is the most heterogeneous

thalassaemia population in the thalassaemia population in the worldworld

Most Common Most Common Thalassaemia Thalassaemia Mutations in UAEMutations in UAE

Mediterranean mutationsMediterranean mutationsCd 39 (c>T)Cd 39 (c>T)IVS-11-1 (G>A)IVS-11-1 (G>A)Cd5 ( -ct)Cd5 ( -ct)IVS-1 (G>A)IVS-1 (G>A)Cd 30 (G > C)Cd 30 (G > C)

Indian mutationsIndian mutationsIVS-1-5 (G>C)IVS-1-5 (G>C)Cd 8/9 (+G)Cd 8/9 (+G)Hb DHb D

Iranian and Eastern Arabian Peninsula mutationsIranian and Eastern Arabian Peninsula mutations-25 bpdel-25 bpdelcd 39 c>Tcd 39 c>TIVS-11-1 (G>A)IVS-11-1 (G>A)

Relatively Common AR disorders in the Relatively Common AR disorders in the Middle EastMiddle East

Disorders that are seen more frequently in Disorders that are seen more frequently in

the population of the Middle east than in the population of the Middle east than in

other populations. Examples:other populations. Examples: Joubert syndromeJoubert syndrome Meckel syndrome Meckel syndrome Bardet-Biedl syndromeBardet-Biedl syndrome

Joubert SyndromeJoubert Syndrome

Hypoplasia/Hypoplasia/dysplasia of the dysplasia of the cerebellar vermiscerebellar vermis

HyperventilationHyperventilation AtaxiaAtaxia Abnormal eye Abnormal eye

movementmovement Mental retardationMental retardation

Molar Tooth MalformationMolar Tooth Malformation

Malformed cerebellar Malformed cerebellar vermisvermis

Thick and elongated Thick and elongated cerebellar pedunclescerebellar peduncles

Deep interpeduncular Deep interpeduncular fossafossa

Joubert Syndrome in UAEJoubert Syndrome in UAE

40 children from 20 families were 40 children from 20 families were

evaluatedevaluated 4 genes were mapped in some of these 4 genes were mapped in some of these

familiesfamilies

JBTS1 – 9q34.3JBTS1 – 9q34.3

JBTS2 – 11p12-q13.3JBTS2 – 11p12-q13.3

JBTS3 - 6q23 [Mutation in AHI1(Jouberin)]JBTS3 - 6q23 [Mutation in AHI1(Jouberin)]

JBTS5- 12q [Mutation in CEP290 gene]JBTS5- 12q [Mutation in CEP290 gene]

Examples of Genetic Disorders that Cluster in Examples of Genetic Disorders that Cluster in Certain Communities in the Middle EastCertain Communities in the Middle East

DisorderDisorderOMIM OMIM NoNo

CommunityCommunity

Faciodigitogenital SyndromeFaciodigitogenital Syndrome227330227330Bedouin tribe in KuwaitBedouin tribe in Kuwait

Hypophosphataemic rickets and Hypophosphataemic rickets and hypercalcuriahypercalcuria

241530241530Bedouin tribe in Israel Bedouin tribe in Israel and Palestinian and Palestinian territoriesterritories

Canavan’s diseaseCanavan’s disease271900271900Samaritans in West Samaritans in West BankBank

Usher Syndrome Type IUsher Syndrome Type I276900276900Samaritans in West Samaritans in West BankBank

Stuve-Wiedemann SyndromeStuve-Wiedemann Syndrome601559601559Omani and Yemeni Omani and Yemeni isolates in UAEisolates in UAE

Ehlers-Danlos Syndrome VIAEhlers-Danlos Syndrome VIA225400225400UAE BedouinUAE Bedouin

Ataxia TelangiectasiaAtaxia Telangiectasia208900208900DruzeDruze

Stüve-Wiedemann Syndrome (SWS)Stüve-Wiedemann Syndrome (SWS)

Stüve and Wiedemann 1971Stüve and Wiedemann 1971

CamptomeliaCamptomelia

CamptodactylyCamptodactyly

Contractures of Contractures of

large jointslarge joints

HyperthemiaHyperthemia Respiratory Respiratory

insufficiencyinsufficiency Feeding and Feeding and

swallowing swallowing difficultiesdifficulties

Early lethalityEarly lethality

Molecular aspect of SWSMolecular aspect of SWS

Caused by Mutations in the LIFR Caused by Mutations in the LIFR gene gene

More than 14 mutations in the LIFR More than 14 mutations in the LIFR gene have been described in the gene have been described in the literatureliterature

SWS in the UAESWS in the UAE

35 cases from 21 families 35 cases from 21 families

originating from Oman and Yemenoriginating from Oman and Yemen

A founder mutation in LIFR gene A founder mutation in LIFR gene

(653_654 ins T) at exon 6, 2 codons (653_654 ins T) at exon 6, 2 codons

downstream predicting premature downstream predicting premature

termination of translationtermination of translation

Ehlers-Danlos Syndrome VIA (EDS Ehlers-Danlos Syndrome VIA (EDS VIA) Kyphoscoliotic EDSVIA) Kyphoscoliotic EDS

Severe muscular hypotonia at birthSevere muscular hypotonia at birth

Severe joint hypermobilitySevere joint hypermobility

Progressive kyphoscoliosisProgressive kyphoscoliosis

Fragility of skin with abnormal scarringFragility of skin with abnormal scarring

Deficiency of the enzyme lysyle hydroxylaseDeficiency of the enzyme lysyle hydroxylase

More than 20 mutations in LH (PLOD1) gene More than 20 mutations in LH (PLOD1) gene

have been described in the literaturehave been described in the literature

EDS VIA in UAEEDS VIA in UAE

16 children with EDS VIA from 12 16 children with EDS VIA from 12 Bedouin UAE families originating Bedouin UAE families originating from 2 tribesfrom 2 tribes

A founder mutation in LH gene was A founder mutation in LH gene was found in affected families (g.23939 found in affected families (g.23939 C>T causing a p.R319X nonsense C>T causing a p.R319X nonsense mutation)mutation)

Rare AR disorders which are limited to Rare AR disorders which are limited to

1 or 2 extended families1 or 2 extended families

Donnai – Barrow SyndromeDonnai – Barrow Syndrome

1st described in 1993 ( Donnai & 1st described in 1993 ( Donnai & Barrow)Barrow)

Diaphragmatic herniaDiaphragmatic hernia ExomphalosExomphalos Distinctive faceDistinctive face Absent corpus callosumAbsent corpus callosum Sensorineural hearing lossSensorineural hearing loss 10 cases reported in the literature10 cases reported in the literature

HypertelorisHypertelorismm

++++++++++

ACCACC----++++

OmphalocelOmphalocelee

++++----++

SNHLSNHL++++++++

CDHCDH----++--CDD, lung CDD, lung hypoplasiahypoplasia

Eye abn.Eye abn.High High myopiamyopia

High myopiaHigh myopiaLarge Large prominent prominent

eyeseyes

Iris coloboma, Iris coloboma, Retinal Retinal

dystrophydystrophy

Retinal Retinal dystrophydystrophy

MiscMiscDilated lat. Dilated lat. ventriclesventricles

Dilated lat. Dilated lat. ventricles, ventricles, AlbinismAlbinism

NND, Large NND, Large AF, No AF, No autopsyautopsy

Speech delaySpeech delayRib/vertebral Rib/vertebral anom, Dev anom, Dev deldel

Brain anom..Brain anom..

Molecular aspect of DBSMolecular aspect of DBS

Homozygosity mapping in the UAE family Homozygosity mapping in the UAE family

localized the gene on chromosome 2q23.3-q31localized the gene on chromosome 2q23.3-q31

Mutations in the LRP2 gene coding Megalin were Mutations in the LRP2 gene coding Megalin were

identifiedidentified

The mutation in the UAE family – c.7564T>CThe mutation in the UAE family – c.7564T>C

p.Y2522Hp.Y2522H

New AR disorders diagnosed in New AR disorders diagnosed in the Middle Eastthe Middle East

I

II

III

A New Autosomal Recessive Mental Retardation Syndrome

A New Autosomal Recessive Syndrome

Mental Retardation

Ocular Colobomas

Brain Malformation

Endocrine Abnormalities

Ichthyosis/dry skin

CHIME SyndromeCHIME Syndrome Zunich & Kaye 1983Zunich & Kaye 1983

Ocular Colobomas

Heart Defect

Ichthyosis

Mental Retardation

Abnormal Ears

6 cases reported in the literature

Molecular study of the CHIME-like Molecular study of the CHIME-like syndromesyndrome

Homozygosity mapping localized the Homozygosity mapping localized the gene to chromosome 4 (LOD score gene to chromosome 4 (LOD score 4.2)4.2)

A mutation in one of the candidate A mutation in one of the candidate genes was identifiedgenes was identified

Functional studies are in progressFunctional studies are in progress

Mental Retardation Mental Retardation Optic AtrophyOptic Atrophy Iris ColobomaIris Coloboma Dry Itchy SkinDry Itchy Skin

Larsen-like Syndrome

Flat faceFlat face HypertelorismHypertelorism Downslanting Palpebral Downslanting Palpebral

fissuresfissures Short webbed neckShort webbed neck

New Larsen-Like SyndromeNew Larsen-Like Syndrome

Larsen-Like SyndromeLarsen-Like Syndrome

Dislocation of elbowsDislocation of elbows Multiple subluxations of the Multiple subluxations of the

interphalangeal joints of fingers and toesinterphalangeal joints of fingers and toes Metatarsus varusMetatarsus varus

Molecular study of Larsen-like Molecular study of Larsen-like syndromesyndrome

Homozygosity mapping localized the Homozygosity mapping localized the gene to chromosome 11gene to chromosome 11

Several candidate genes were Several candidate genes were sequencedsequenced

Mutation in one of these genes was Mutation in one of these genes was identifiedidentified

Functional studies are in progressFunctional studies are in progress

1

4

25

Autosomal Recessive MR SyndromeNoonan-like

Autosomal Recessive MR SyndromeNoonan-like

Moderate to severe MRMacrocephaly

Short statureFacial Dysmorphism:

arched eyebrowsnose asymmetrydental malocculsionlong face Low-set ears

Short neckChest deformityDry skin

3 of 7 have congenital heart defects

Molecular study in Noonan-like syndrome

Homozygosity mapping localized the gene to chromosome 20 (LOD Score 6.2)

Several candidate genes were sequenced, no mutation has been identified yet

Genetic Prevention Programmes of AR Genetic Prevention Programmes of AR Disorders in the Middle EastDisorders in the Middle East

Premarital carrier screeningPremarital carrier screening

Family oriented approachFamily oriented approach

Antenatal scanningAntenatal scanning

Pre-implantation diagnosisPre-implantation diagnosis

EducationEducation

Causes of Ineffective Genetic Counseling in the Middle East

Cultural – Consanguineous marriages

– Large family size

Local beliefs Legal issues

– Options are not available since they are legally unacceptable

Attitudes toward Genetic Counseling in UAE

100 couples 50 acknowledge a genetic basis for their child’s

condition 10 only remembered the risk given to them 50 preferred consanguineous marriages for

themselves and their children 10 agreed with prenatal diagnosis and abortion of

affected pregnancies 75 agreed with carrier screening and

preconception diagnosis in affected families

ConclusionConclusion

AR disorders are common in the Middle EastAR disorders are common in the Middle East Most AR disorders in the Middle East are not Most AR disorders in the Middle East are not

studiedstudied The Middle East will continue to be a source The Middle East will continue to be a source

of new information about AR disorders for of new information about AR disorders for the whole worldthe whole world

More work need to be done in planning and More work need to be done in planning and implementing ways of prevention and implementing ways of prevention and treatment of AR disorders in the Middle Easttreatment of AR disorders in the Middle East

AcknowledgementAcknowledgement

Christopher Walsh- Harvard medical school, USAChristopher Walsh- Harvard medical school, USA Barbara Pober- Harvard medical school, USABarbara Pober- Harvard medical school, USA Joseph Gleeson- UCSD, USAJoseph Gleeson- UCSD, USA Stefan Mundlos – Max Plank Institute for Stefan Mundlos – Max Plank Institute for

Molecular Medicine, GermanyMolecular Medicine, Germany Kathrin Hoffman-Humboldt university, GermanyKathrin Hoffman-Humboldt university, Germany Valarie Cormier-Daire- INSERM, FranceValarie Cormier-Daire- INSERM, France Beat Steinmann – Children’s hospital, SwitzerlandBeat Steinmann – Children’s hospital, Switzerland Bassam Ali- FMHS,UAEBassam Ali- FMHS,UAE

Al Ain International Genetics Conference – October 2008

www.fmhs.uae.ac.ae