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
Country
Consanguinity
Average Inbreeding Coefficient
Bahrain
31.8 – 44.5 –
Egypt 29
0.0101
Iraq
46.4
0.0225
Israeli Arabs
20.6 – 52.9 –
Jordan
25.6 – 52.1 –
Kuwait
54.3
0.0219
Lebanon
16.5 – 29.6
0.0088
Oman
35.9
0.0198
Qatar 54
Saudi Arabia
41.4 – 51.7 –
UAE
50.5
0.0222
Yemen
40 – 44.7 –

8. Number of genetic disorders in Arabs - 806
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

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
Country
thal carrier
thal carrier
Sickle Cell Trait
Bahrain
2.9
24.2
13.8
Egypt
4.5 NA
Iraq
4.6
6.5 – 16
Jordan
3 – 5.9
2 – 3.5
0.5 – 6
Kuwait
5 – 10
Lebanon 2
0.3
Oman
2.2 – 4
5.8 – 10
Saudi Arabia
1 – 15
1 – 25
UAE
8.3 49
1.4

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
Mediterranean mutations
Cd 39 (c>T)
IVS-11-1 (G>A)
Cd5 ( -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

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
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
Stuve-Wiedemann Syndrome
601559
Omani and Yemeni isolates in UAE
Ehlers-Danlos Syndrome VIA
225400
UAE Bedouin
Ataxia Telangiectasia
208900
Druze

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 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

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

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 Syndrome Zunich & 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. Autosomal Recessive MR Syndrome4 2 1 5
Autosomal Recessive MR Syndrome
Noonan-like

44. 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

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

51. Al Ain International Genetics Conference – October 2008