Autosomal recessive disorders: the Middle East perspective - PowerPoint PPT Presentation

View by Category
About This Presentation
Title:

Autosomal recessive disorders: the Middle East perspective

Description:

Autosomal recessive disorders: the Middle East perspective – PowerPoint PPT presentation

Number of Views:161
Avg rating:3.0/5.0
Slides: 52
Provided by: lihadha
Learn more at: http://www.bibalex.org
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: 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
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
8
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

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

10
(No Transcript)
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 NA
Iraq 4.6 NA 6.5 16
Jordan 3 5.9 2 3.5 0.5 6
Kuwait NA 5 10 NA
Lebanon 2 NA 0.3
Oman 2.2 4 NA 5.8 10
Saudi Arabia 1 15 5 10 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 (cgtT) IVS-11-1 (GgtA) Cd5 ( -ct) IVS-1 (GgtA) Cd 30 (G gt C)
Indian mutations IVS-1-5 (GgtC) Cd 8/9 (G) Hb D
Iranian and Eastern Arabian Peninsula mutations -25 bpdel cd 39 cgtT IVS-11-1 (GgtA)
14
(No Transcript)
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
Disorder OMIM No Community
Faciodigitogenital Syndrome 227330 Bedouin tribe in Kuwait
Hypophosphataemic rickets and hypercalcuria 241530 Bedouin tribe in Israel and Palestinian territories
Canavans 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
20
Stüve-Wiedemann Syndrome (SWS) Stüve and
Wiedemann 1971
  • Camptomelia
  • Camptodactyly
  • Contractures of large joints
  • Hyperthemia
  • Respiratory insufficiency
  • Feeding and swallowing difficulties
  • Early lethality

21
(No Transcript)
22
(No Transcript)
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

26
(No Transcript)
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 CgtT 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
Hypertelorism
ACC - -
Omphalocele - -
SNHL
CDH - - - CDD, lung hypoplasia
Eye abn. High myopia 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.7564TgtC
  • 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

35
(No Transcript)
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
4
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 childs
    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 Childrens hospital, Switzerland
  • Bassam Ali- FMHS,UAE

51
Al Ain International Genetics Conference
October 2008 www.fmhs.uae.ac.ae
About PowerShow.com