Autosomal recessive disorders: the Middle East perspective

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

2. DEFINITION OF THE MIDDLE EAST Lancet Vol 367, 2006

3. UNITED ARAB EMIRATES

4. Burj Al Arab in Dubai

5. Faculty of Medicine and Health Sciences United Arab Emirates University

6. 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

7. Consanguinity Rates and Inbreeding Coefficients in the Middle East

8. Autosomal Recessive disorders in ArabsThe 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

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

11. Prevalence of Haemoglobinopathies in the Middle East

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

13. Most Common  Thalassaemia Mutations in UAE

15. 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

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

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

18. Joubert Syndrome in UAE • 40 children from 20 families were evaluated • 4 genes were mapped in some of these families JBTS1 – 9q34.3 JBTS2 – 11p12-q13.3 JBTS3 - 6q23 [Mutation in AHI1(Jouberin)] JBTS5- 12q [Mutation in CEP290 gene]

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

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

23. 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

24. 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

25. 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 (PLOD1) gene have been described in the literature

27. 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.R319X nonsense mutation)

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

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

31. Molecular aspect of DBS • Homozygosity mapping in the UAE family localized the gene on chromosome 2q23.3-q31 • Mutations in the LRP2 gene coding Megalin were identified • The mutation in the UAE family – c.7564T>C p.Y2522H

32. New AR disorders diagnosed in the Middle East

33. I II III A New Autosomal Recessive Mental Retardation Syndrome

34. A New Autosomal Recessive Syndrome • Mental Retardation • Ocular Colobomas • Brain Malformation • Endocrine Abnormalities • Ichthyosis/dry skin

36. CHIME SyndromeZunich & Kaye 1983 • Ocular Colobomas • Heart Defect • Ichthyosis • Mental Retardation • Abnormal Ears 6 cases reported in the literature

37. 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

38. Mental Retardation • Optic Atrophy • Iris Coloboma • Dry Itchy Skin

39. Larsen-like Syndrome

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

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

42. 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

43. 4 2 1 5 Autosomal Recessive MR Syndrome Noonan-like

44. Autosomal Recessive MR SyndromeNoonan-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

45. 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

46. Genetic Prevention Programmes of AR Disorders in the Middle East • Premarital carrier screening • Family oriented approach • Antenatal scanning • Pre-implantation diagnosis • Education

47. 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

48. 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

49. 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

50. 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