Download Autosomal recessive disorders: the Middle East perspective

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
 AR disorders that cluster in certain
communities
 AR disorders which are limited to 1 or 2
extended families
 New AR disorders
Rates of common single gene disorders in Arab Countries
Beta
Betathalassemia
thalassemia
carrier
carrierrate
rate
Up
to
15%
Up to 15%
Familial
FamilialMediterranean
Mediterranean
Fever
carrier
Fever carrierrate
rate
Up
to
18%
Up to 18%
Up
Uptoto27%
27%ofofmales
males
have
have
G6PD
deficiency
G6PD deficiency
Common
Commonsingle
single
gene
disorders
gene disordersinin
Arab
Arabcountries
countries
Alpha
Alphathalassemia
thalassemia
carrier
carrierrate
rate
Up
to
49%
Up to 49%
Sickle
Sicklecell
cellcarrier
carrierrate
rate
Up
to
25%
Up to 25%
??Deaf-mutism
Deaf-mutism
??Congenital
Congenitaladrenal
adrenal
hyperplasia
hyperplasia
Prevalence of Haemoglobinopathies
in the Middle East
Country
thal carrier thal carrier
Sickle Cell
Trait
Bahrain
Egypt
Iraq
2.9
4.5
4.6
24.2
NA
NA
13.8
NA
6.5 – 16
Jordan
Kuwait
Lebanon
Oman
3 – 5.9
NA
2
2.2 – 4
2 – 3.5
5 – 10
NA
NA
0.5 – 6
NA
0.3
5.8 – 10
5 – 10
49
1 – 25
1.4
Saudi Arabia 1 – 15
UAE
8.3
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)
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
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
JBTS1 – 9q34.3
JBTS2 – 11p12-q13.3
JBTS3 - 6q23 [Mutation in AHI1(Jouberin)]
JBTS5- 12q [Mutation in CEP290 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 (PLOD1) 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.R319X nonsense mutation)
Rare AR disorders which are limited
to 1 or 2 extended families
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
Hyperteloris
m
+
+
ACC
-
-
Omphalocele
+
+
SNHL
+
+
CDH
-
-
High myopia
High myopia
Eye abn.
Misc
Dilated lat.
ventricles
Dilated lat.
ventricles,
Albinism
+
+
+
+
+
-
+
+
+
+
-
CDD, lung
hypoplasia
Large
prominent eyes
Iris coloboma,
Retinal dystrophy
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 2q23.3-q31
 Mutations in the LRP2 gene coding Megalin
were identified
 The mutation in the UAE family – c.7564T>C
p.Y2522H
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