Autosomal recessive disorders the Middle East perspective Lihadh

Autosomal recessive disorders: the Middle East perspective Lihadh Al-Gazali Faculty of Medicine and Health Sciences UAE University

DEFINITION OF THE MIDDLE EAST Lancet Vol 367, 2006

UNITED ARAB EMIRATES

Burj Al Arab in Dubai

Faculty of Medicine and Health Sciences United Arab Emirates University

Characteristics of the population in the Middle East Multi-ethnic & diverse Presence of isolated communities, like Bedouins, Druze, Nubians High mobility Large family size High level of consanguinity

Consanguinity Rates and Inbreeding Coefficients in the Middle East Country Consanguinity Average Inbreeding Coefficient Bahrain 31. 8 – 44. 5 0. 0152 – 0. 0166 Egypt 29 0. 0101 Iraq 46. 4 0. 0225 Israeli Arabs 20. 6 – 52. 9 0. 00993 – 0. 0253 Jordan 25. 6 – 52. 1 0. 0142 – 0. 0284 Kuwait 54. 3 0. 0219 Lebanon 16. 5 – 29. 6 0. 0088 Oman 35. 9 0. 0198 Qatar 54 0. 02706 Saudi Arabia 41. 4 – 51. 7 0. 0196 – 0. 0312 UAE 50. 5 0. 0222 Yemen 40 – 44. 7 0. 0212 – 0. 2442

Autosomal Recessive disorders in Arabs The Catalogue for Transmission Genetics in Arabs (CTGA) Number of genetic disorders in Arabs - 806 Autosomal disorders - 701 AR -513 AD -206 X-Linked disorders - 47 XR -23 XD -10 www. cags. org. ae

Autosomal Recessive (AR) Disorders in the Middle East Common AR disorders Relatively common AR disorders that cluster in certain communities AR disorders which are limited to 1 or 2 extended families New AR disorders

Prevalence of Haemoglobinopathies in the Middle East Country thal carrier Bahrain Egypt 2. 9 4. 5 24. 2 NA Sickle Cell Trait 13. 8 NA Iraq Jordan Kuwait Lebanon Oman 4. 6 3 – 5. 9 NA 2 2. 2 – 4 NA 2 – 3. 5 5 – 10 NA NA 6. 5 – 16 0. 5 – 6 NA 0. 3 5. 8 – 10 Saudi Arabia UAE 1 – 15 8. 3 5 – 10 49 1 – 25 1. 4

Common Genetic Disorders in the UAE Thalassaemia Major health problem in UAE Mutation analysis: UAE is the most heterogeneous thalassaemia population in the world

Most Common Thalassaemia Mutations in UAE Mediterranean mutations Cd 39 (c>T) IVS-11 -1 (G>A) Cd 5 ( -ct) IVS-1 (G>A) Cd 30 (G > C) Indian mutations IVS-1 -5 (G>C) Cd 8/9 (+G) Hb D Iranian and Eastern Arabian Peninsula mutations -25 bpdel cd 39 c>T IVS-11 -1 (G>A)

Relatively Common AR disorders in the Middle East Disorders that are seen more frequently in the population of the Middle east than in other populations. Examples: Joubert syndrome Meckel syndrome Bardet-Biedl syndrome

Joubert Syndrome Hypoplasia/dysplasia of the cerebellar vermis Hyperventilation Ataxia Abnormal eye movement Mental retardation

Molar Tooth Malformation Malformed cerebellar vermis Thick and elongated cerebellar peduncles Deep interpeduncular fossa

Joubert Syndrome in UAE 40 children from 20 families were evaluated 4 genes were mapped in some of these families JBTS 1 – 9 q 34. 3 JBTS 2 – 11 p 12 -q 13. 3 JBTS 3 - 6 q 23 [Mutation in AHI 1(Jouberin)] JBTS 5 - 12 q [Mutation in CEP 290 gene]

Examples of Genetic Disorders that Cluster in Certain Communities in the Middle East Disorder OMIM No Community Faciodigitogenital Syndrome 227330 Bedouin tribe in Kuwait Hypophosphataemic rickets and hypercalcuria 241530 Bedouin tribe in Israel and Palestinian territories Canavan’s disease 271900 Samaritans in West Bank Usher Syndrome Type I 276900 Samaritans in West Bank Stuve-Wiedemann Syndrome 601559 Omani and Yemeni isolates in UAE Ehlers-Danlos Syndrome VIA 225400 UAE Bedouin Ataxia Telangiectasia 208900 Druze

Stüve-Wiedemann Syndrome (SWS) Stüve and Wiedemann 1971 Camptomelia Camptodactyly Contractures of large joints Hyperthemia Respiratory insufficiency Feeding and swallowing difficulties Early lethality

Molecular aspect of SWS Caused by Mutations in the LIFR gene More than 14 mutations in the LIFR gene have been described in the literature

SWS in the UAE 35 cases from 21 families originating from Oman and Yemen A founder mutation in LIFR gene (653_654 ins T) at exon 6, 2 codons downstream predicting premature termination of translation

Ehlers-Danlos Syndrome VIA (EDS VIA) Kyphoscoliotic EDS Severe muscular hypotonia at birth Severe joint hypermobility Progressive kyphoscoliosis Fragility of skin with abnormal scarring Deficiency of the enzyme lysyle hydroxylase More than 20 mutations in LH (PLOD 1) gene have been described in the literature

EDS VIA in UAE 16 children with EDS VIA from 12 Bedouin UAE families originating from 2 tribes A founder mutation in LH gene was found in affected families (g. 23939 C>T causing a p. R 319 X nonsense mutation)

Rare AR disorders which are limited to 1 or 2 extended families

Donnai – Barrow Syndrome 1 st described in 1993 ( Donnai & Barrow) Diaphragmatic hernia Exomphalos Distinctive face Absent corpus callosum Sensorineural hearing loss 10 cases reported in the literature

Hyperteloris m + + ACC - - Omphalocele + + SNHL + + CDH - - High myopia Eye abn. Misc Dilated lat. ventricles, Albinism + + + - CDD, lung hypoplasia Large prominent eyes Iris coloboma, Retinal dystrophy NND, Large AF, No autopsy Speech delay Rib/vertebral anom, Dev del Brain anom. . -

Molecular aspect of DBS Homozygosity mapping in the UAE family localized the gene on chromosome 2 q 23. 3 -q 31 Mutations in the LRP 2 gene coding Megalin were identified The mutation in the UAE family – c. 7564 T>C p. Y 2522 H

New AR disorders diagnosed in the 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 Syndrome Zunich & Kaye 1983 Ocular Colobomas Heart Defect Ichthyosis Mental Retardation Abnormal Ears 6 cases reported in the literature

Molecular study of the CHIME-like syndrome Homozygosity mapping localized the gene to chromosome 4 (LOD score 4. 2) A mutation in one of the candidate genes was identified Functional studies are in progress

Mental Retardation Optic Atrophy Iris Coloboma Dry Itchy Skin

Larsen-like Syndrome

New Larsen-Like Syndrome Flat face Hypertelorism Downslanting Palpebral fissures Short webbed neck

Larsen-Like Syndrome Dislocation of elbows Multiple subluxations of the interphalangeal joints of fingers and toes Metatarsus varus

Molecular study of Larsen-like syndrome Homozygosity mapping localized the gene to chromosome 11 Several candidate genes were sequenced Mutation in one of these genes was identified Functional studies are in progress

4 1 2 5 Autosomal Recessive MR Syndrome Noonan-like

Autosomal Recessive MR Syndrome Noonan-like Moderate to severe MR Macrocephaly Short stature Facial Dysmorphism: arched eyebrows nose asymmetry dental malocculsion long face Low-set ears Short neck Chest deformity Dry 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 Disorders in the Middle East Premarital carrier screening Family oriented approach Antenatal scanning Pre-implantation diagnosis Education

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

Conclusion AR disorders are common in the Middle East Most AR disorders in the Middle East are not studied The Middle East will continue to be a source of new information about AR disorders for the whole world More work need to be done in planning and implementing ways of prevention and treatment of AR disorders in the Middle East

Acknowledgement Christopher Walsh- Harvard medical school, USA Barbara Pober- Harvard medical school, USA Joseph Gleeson- UCSD, USA Stefan Mundlos – Max Plank Institute for Molecular Medicine, Germany Kathrin Hoffman-Humboldt university, Germany Valarie Cormier-Daire- INSERM, France Beat Steinmann – Children’s hospital, Switzerland Bassam Ali- FMHS, UAE

Al Ain International Genetics Conference – October 2008 www. fmhs. uae. ac. ae