collaborative genomics
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Collaborative genomics for human health and cooperation in the Mediterranean regionTayfun Özçelik, Moien Kanaan, Karen B Avraham, Drakoulis Yannoukakos, André Mégarbané, Ghazi O Tadmouri, Lefkos Middleton, Giovanni Romeo, Mary-Claire King & Ephrat Levy-Lahad
the US government has proposed the development of scientific centers of excellence to solve global challenges. We propose such a center of excellence devoted to the genomic analysis of mediterranean populations of all creeds. this genomic focus is rooted in the region’s demographic history, builds on the area’s rapidly developing expertise in human genetics, and will yield scientific discoveries of both local and global significance. the genome sequence data of mediterranean populations will offer unique insights into human evolution and early human migration. the potent combination of highly consanguineous populations in the mediterranean’s southern and eastern rims and regional medical and scientific expertise could lead to the identification and characterization of many genes responsible for human disease. Such discoveries will enable genetic knowledge to be translated into medical knowledge that will benefit local populations and contribute substantially to the understanding of the genetic bases of human diseases worldwide.
In Cairo in June 2009, US President Obama spoke of the importance of international col-laboration for scientific and technological development1. This speech was followed by fact-finding visits by American Science Envoys to the Middle East, North Africa, Europe, and South and Southeast Asia2.
Shared genes and shared cultures are key factors that unite people. As a group of Mediterranean geneticists committed to addressing local genetic issues and to borderless global scientific collaboration3, we welcome the US initiative. We propose that human genomics is an excellent common resource for addressing common challenges and for deepening existing scientific relationships in the Mediterranean basin across all countries and populations.
In this commentary, following discussions held during the Mediterranean Medical Genetics
Meeting (MediMedGen) at Bilkent University in Ankara in June 2009, we propose a genom-ics initiative consisting of collaborative studies in human genomics that can provide a solid foundation to the American Science Envoys Program, with practical benefit to people in the region and worldwide.
A vision for Mediterranean collaboration in human genomicsSequencing the human genome generated a landmark scientific resource that provides a common platform for biomedical research. To realize the promise of genomic medi-cine will require further advances on several fronts, including reductions in sequencing and data analysis costs to enable many more individual sequences to be generated, more complete annotation of the human genome
Tayfun Özçelik is at the Department of Molecular Biology and Genetics, Faculty of Science & Institute of Materials Science and Nanotechnology (UNAM), Bilkent University, Ankara, Turkey. Moien Kanaan is at the Department of Life Sciences, Bethlehem University, Bethlehem, Palestine. Karen B. Avraham is at the Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Drakoulis Yannoukakos is at the Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research ‘Demokritos’, Aghia Paraskevi, Athens, Greece. André Mégarbané is at the Unité de Génétique Médicale, and the INSERM, Laboratoire International Associé à l’UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Ghazi O. Tadmouri is at the Centre for Arab Genomic Studies, Dubai, United Arab Emirates. Lefkos Middleton is at the School of Public Health, Imperial College, London, UK. Giovanni Romeo, President of the European Genetics Foundation, is at the Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy. Mary-Claire King is at the Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. Ephrat Levy-Lahad is at the Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel. Correspondence to T.Ö. ([email protected]) or E.L.-L. ([email protected]).
sequence, the creation of additional compu-tational tools and databases, the translation of human genomic research into clinical prac-tice, the delivery of services through national health systems, the development and training of a skilled workforce, and consideration of the ethical, social and legal issues that accom-pany these innovations4.
Although local issues exist, these challenges are global. The human genomics initiative for the Mediterranean region that is proposed here makes a unique contribution to science and medicine because it takes advantage of the specific strengths and characteristics of the region’s population and undertakes an inte-grated approach, using both whole-genome sequencing of Mediterranean individuals and family-based studies to identify genes for spe-cific diseases.
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Whole genome sequencing in Mediterranean individualsWhole genome sequencing of individuals from the Mediterranean basin has not yet been performed, even though the region was one of the first stations of human migration out of Africa. Indeed, Mediterranean individuals have exerted both genetic and cultural influ-ence well beyond their ancestral home. The complete genome sequences reported so far have been for individuals of ancestries from Northwest Europe, China, Korea and sub-Saharan Africa. Although the international 1,000 Genomes Project will create a more detailed picture of human genetic variation (http://www.1000genomes.org/page.php), whole-genome sequencing of individuals from Mediterranean populations will reveal new information on human evolution, migra-tion and diversity.
Sequencing a sufficient number of rep-resentative Mediterranean individuals will provide a reference and scaffold for fur-ther genetic studies in the region. As rapid advances in DNA sequencing technology have led to marked reductions in cost as well as profound improvements in efficiency over the last decade, there are now many sequenc-ing centers worldwide, including in the Mediterranean basin. This capacity could be further developed and exploited to contribute to the understanding of human genetic varia-tion in a concerted fashion. It would be feasible to generate a comprehensive Mediterranean catalog of single nucleotide and small inser-tion-deletion polymorphisms and copy num-ber variations, with corresponding allele and haplotype frequencies and linkage disequilib-rium patterns. Performing such studies locally will lead the regional community into the next stage of genomic studies. To ensure free and open access to the data generated, a virtual database, Genotheca Mediterranea, could be established.
It has become increasingly difficult to define mutations as causative as the extent of human variation has been revealed. There is a renewed realization that one means of addressing this complexity is by linking func-tional mutations with specific phenotypes, a link that is highlighted, often in stark relief, by recessive diseases. Although in most pop-ulations recessive deleterious mutations will never be fully expressed, such mutations and their effects become clearly evident in con-sanguineous populations, where individuals homozygous for a deleterious trait are signifi-cantly more common. In this respect, studies in Mediterranean populations can provide a new genotype-phenotype map of the human genome.
Consanguinity and disease gene identification in Mediterranean populationsThe southern and eastern rims of the Mediterranean basin have among the high-est levels of consanguinity in the world, comprising part of a region of consanguin-ity that extends from the southern shores of the Mediterranean Sea through the Middle East, Mesopotamia, the Gulf and the Indian subcontinent to Southeast Asia. The roots of consanguinity in Mediterranean populations date to ancient times5, reflecting both historical and contemporary social preferences for mar-riages between relatives. The social and cultural advantages of this practice include mainte-nance of family structure and property, and financial advantages relating to dowry. Better relations with in-laws, and the perception that consanguineous marriages might be more stable than marriages between non-relatives, are also important. At present, in many areas of the region ~25% of marriages are between first cousins. True rates of consanguinity are even higher because there is additional endogamy (that is, marriage within the extended clan; hamuleh in Arabic, hısım in Turkish)6, lead-ing to homozygosity rates greater than those predicted by the degree of kinship alone7. By contrast, consanguinity on the northern rim of the Mediterranean basin is generally low.
Consanguinity has a direct impact on the frequency of recessive diseases. With multiple layers of consanguinity, the number of indi-viduals affected with any recessive disease is proportional to the disease allele frequency. By contrast, in a large, randomly mating pop-ulation, the number of affected individuals is proportional to the square of the disease allele frequency8. Coupled with the large family size that is characteristic of the southern rim of the Mediterranean and the Middle East, this statis-tic results in increased frequency of recessive disease, creating human and medical chal-lenges, but also the scientific opportunities to address them.
Recessive diseases in consanguineous com-munities vary in frequency, based on the ages of the mutations responsible for them and selec-tive pressures on the phenotype9. The hemo-globinopathies, G6PD deficiency and familial Mediterranean fever are frequent throughout the region. Inherited hearing loss, Bardet-Biedl syndrome and Meckel Gruber syndrome are frequent in many communities in the region. Other conditions appear in a local community or clan, or specifically in one family. The num-ber of diseases is very large, because any muta-tion that is not lethal early in pregnancy can be revealed through consanguinity. Many of these traits, particularly the most rare, have not yet
been studied. For example, of the 577 reces-sive diseases that have been reported in Arab families (http://www.cags.org.ae/ctga_search.html), the responsible loci are not known for 168. Many other recessive diseases, especially those confined to single families, are not even reported.
The gap in identifying genes responsi-ble for Mendelian diseases is not unique to Mediterranean populations: the molecular bases of at least 3,800 known or suspected Mendelian diseases are unknown (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim). Southern and eastern Mediterranean populations are unique in that for recessive traits in consanguineous communities, identification of the causative genes is eminently feasible using homozygosity mapping and sequencing. The success of this approach can be seen from the large number of disease genes that have been identified by study-ing Mediterranean families (Table 1).
Current genomics research in the Mediterranean basinMolecular studies of disease genes began in the 1980s with the identification of the muta-tion spectrum of X-linked diseases such as Duchenne/Becker muscular dystrophy and hemophilia, and recessive diseases such as the thalassemias, phenylketonuria and cystic fibrosis. These studies extended in the 1990s to linkage mapping of rare diseases, and have evolved today to homozygosity mapping using SNP arrays, which is powerful enough to identify disease loci even in families too small to obtain meaningful results using tradi-tional linkage approaches10. In the early years genetic analysis of Mediterranean families was often performed outside the region, in col-laborations with American and European cen-ters. However, over time these collaborations have evolved and genetic analyses are increas-ingly performed in regional laboratories. Examples of genes that have been identified in the region include those responsible for deaf-ness (FGF3, MYO3A, OTOA, OTOF, POU4F3, SERPINB6, TECTA, TRIOBP, WHRN), neu-rodevelopmental disorders (ALS2, FA2H, FGD4, SNAP29, VLDLR, VRK1) and other rare diseases (ALX1, BBS10, CHST14, DDR2, SLC34A2, TAC3, TACR3) (see Table 1 for a comprehensive list). In parallel, biobanks and genomic databases funded through governmental research programs have been established in several countries in the region, with active participation in Orphanet (http://www.orpha.net/consor/cgi-bin/index.php), the EU-funded portal for rare diseases and orphan drugs. If properly supported, these developments in general and local capacity are likely to lead to an explosion in gene discovery
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which in the near future might be limited only by the phenotype discovery rate.
World Health Organization statistics indi-cate that the global burden of disease is shifting from infectious to noncommunicable diseases11. Many of these diseases are genetically influ-enced. The responsible genes can be identified using population resources and tools now at hand. A concentrated effort to solve the genetic bases of noncommunicable diseases will have an important public health impact far beyond the specific alleles identified in the first families to be studied. The genetic dissection of well char-acterized disease phenotypes in large kindreds will reveal genes that underlie complex, hetero-geneous diseases. Indeed, pathways relevant to common diseases are often identified through genes responsible for related rare disorders12.
Translating human genomic research into clinical practiceAs a consequence of consanguinity, the preva-lence at birth of severe congenital genetic disor-ders in the eastern Mediterranean is among the highest in the world: >65 affected children per 1,000 live births13. From a regional perspective, programs that address recessive diseases have a high priority and need to go beyond gene identi-fication to the characterization of the mutational spectrum relevant to each locale, and to the pro-vision of community-based medical genetics services. This extremely sensitive issue, owing to its ethical, legal and social aspects, can best be addressed by professionals from the same cul-tures as the affected families, and this is most likely to lead to clinically effective outcomes. From a global perspective, this agenda is rele-vant to the challenges of the post-genome era14, especially in the fields of personalized medicine and identification of new drug targets emerg-ing from genomic analysis of common and rare diseases. According to currently available statistics, more than 1,500 laboratories perform genetic tests in the EU, and the annual growth in testing is close to 300%. With a population size comparable to the EU, the development, harmonization, validation and standardization of genetic testing services is a high-priority area in the Mediterranean basin.
The implementation and delivery of services through national health systems is not easy, but the large and diverse populations of the Mediterranean basin have access to excellent universities, institutes and clinics. In many parts of the region, medical genetics is a recognized clinical specialty or sub-specialty, strengthened by highly trained dysmorphologists, pediatri-cians and human geneticists. Close collaboration with the European Society of Human Genetics, the American Society of Human Genetics and the American College of Medical Genetics has
led to many national and regional congresses, workshops, and symposia focused on training, education, and workforce planning in medi-cal genetics. Future MediMedGen meetings are planned, including one in Cyprus in 2011. The Mediterranean basin is also the home of the European Genetics Foundation, which organizes regular courses in genetic medicine, attended by more than 6,000 students over the last two decades (http://www.eurogene.eu/). To address the standardization and harmo-nization of genetics services, Mediterranean geneticists have taken active roles in projects such as EuroGenTest (http://www.eurogentest.org/), MedGenMed and MedGeNet (http://www.eurogene.eu/), through which resources for assessing and addressing ethical, social and legal issues are also available (http://www.cags.org.ae/ctga_search.html). Finally, progress in the computational use of medical and genomic data is reflected in genetic and genomic data-bases of Mediterranean populations that have already been launched15. We predict that these assets will be crucial for the integration of genet-ics research into the delivery of health outcomes in the region and the world.
A plan for the futureOn the basis of these considerations, we pro-pose an international collaborative Center of Excellence for Genomics Research in the Mediterranean region, supported by inter-national and national funding agencies. We suggest that this Center of Excellence be geo-graphically decentralized and function as a network of researchers and genomics research centers whose primary remit would be to sup-port and facilitate joint research proposals. Members of the Center would include sci-entists from the region and those supporting the development of genomics in the region. They would engage in projects centered in Mediterranean laboratories whenever pos-sible, and involving transfer of technology and training, to make the Mediterranean focus increasingly realistic with time.
There is much greater strength in using resources to support science in existing insti-tutions rather than creating a new physical structure. A decentralized, international, col-laborative, investigator-initiated model alle-viates hurdles of bureaucracy and facilitates international decision-making. We believe that work to facilitate the generation of whole-genome sequence data from representative Mediterranean populations, and the discovery and characterization of genes based on well defined phenotypes in large kindreds and/or consanguineous families, should be scientifi-cally and socially attractive to funding agen-cies within and beyond the Mediterranean
region. A wide range of human traits, both rare and common, could be evaluated. The proposed scientific structure and objectives are excellent models and realistic goals for collaborative genomics for human health and cooperation in the Mediterranean basin, and could have an important impact on public health.
ConclusionDuring the past two decades, working with families from the Mediterranean region, sci-entists from Algeria, Cyprus, Egypt, France, Greece, Israel, Italy, Jordan, Lebanon, Morocco, Palestine, Tunisia and Turkey have collaborated with each other and with geneticists worldwide to identify the genes responsible for many inher-ited diseases, both common and rare. Active collaborations across the region are presently exploring human genomic variation to bet-ter understand susceptibility and resistance to disease. These projects demonstrate the shared culture and goals of human genetics, and serve as a testimony to the commitment to interna-tional collaboration. The present interest of the US government encourages us to take another important step in these efforts.
ACKNOWLEDGMENTSThis Commentary is dedicated to the memory of Ihsan Dogramaci, a pioneer and reformer in child health and higher education, one of the founders of WHO, the longest serving Executive Board member of UNICEF and a tireless campaigner for world peace.
COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.
1. Lee, J. The President’s speech in Cairo: a new begin-ning. The White House Blog <http://www.whitehouse.gov/Blog/NewBeginning> (2009).
2. Anonymous. Secretary Clinton announces global part-nerships to advance Cairo’s ‘New Beginning’. The US Department of State <http://www.state.gov/r/pa/prs/ps/2009/nov/131232.htm> (2009).
3. Anonymous. Editorial. Nat. Genet. 41, 861 (2009).4. House of Lords Science and Technology Committee.
Genomic medicine vol. 1: report. <http://www.publications.parliament.uk/pa/ld200809/ldselect/ldsctech/107/107i.pdf> (2009).
5. Hawass, Z. et al. J. Am. Med. Assoc. 303, 638–647 (2010).
6. Tadmouri, G.O. et al. Reprod. Health 6, 17 (2009).7. Woods, C.G. et al. Am. J. Hum. Genet. 78, 889–896
(2006).8. Lander, E.S. & Botstein, D. Science 236, 1567–1570
(1987).9. Zlotogora, J. Am. J. Med. Genet. 109, 176–182
(2002).10. Shahin, H. et al. Eur. J. Hum. Genet. 18, 407–413
(2010).11. World Health Organization. The global burden of
disease: 2004 update. <http://www.who.int/health-info/global_burden_disease/2004_report_update/en/index.html> (2004).
12. McClellan, J. & King, M.C. Cell 141, 210–217 (2010).
13. Alwan, A. & Modell, B. Nat. Rev. Genet. 4, 61–68 (2003).
14. Collins, F. Nature 464, 674–675 (2010).15. Tadmouri, G.O. Al Ali, M.T., Al-Haj Ali, S. & Al Khaja,
N. Nucleic Acids Res. 34, D602–D606 (2006).
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. 34,
20
3–2
08
(2
00
3)
Fron
tona
sal d
yspl
asia
NA
ALX1
Turk
eyAm
. J. H
um. G
enet
. 86,
78
9–7
96
(2
01
0)
H s
yndr
ome
61
23
91
SLC2
9A3
Isra
el (
Pal
esti
nian
), B
ulga
ria
Am. J
. Hum
. Gen
et. 8
3, 5
29
–53
4 (
20
08
)
Hyp
eros
tosi
s-hy
perp
hosp
hate
mia
syn
drom
e6
10
23
3G
ALN
T3Is
rael
(D
ruze
), P
ales
tine
J. M
ol. M
ed. 8
3, 3
3–3
8 (
20
05
)
Hyp
ogon
adot
ropi
c hy
pogo
nadi
sm1
46
11
0TA
C3, T
ACR
3Tu
rkey
Nat
. Gen
et. 4
1, 3
54
–35
8 (
20
09
)
Hyp
otri
chos
is, c
onge
nita
l, w
ith
juve
nile
mac
ular
dys
trop
hy6
01
55
3CD
H3
Isra
el (
Dru
ze)
Nat
. Gen
et. 2
9, 1
34
–13
6 (
20
01
)
Icht
hyos
is, l
amel
lar
36
04
77
7CY
P4F2
2A
lger
ia, F
ranc
e, I
taly
, Leb
anon
Hum
. Mol
. Gen
et. 1
5, 7
67
–77
6 (
20
06
)
Icht
hyos
is w
ith
hypo
tric
hosi
s, a
utos
omal
rec
essi
ve6
10
76
5ST
14Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et. 8
0, 4
67
–47
7 (
20
07
)
Jalil
i syn
drom
e2
17
08
0CN
NM
4K
osov
o, L
eban
onAm
. J. H
um. G
enet
. 84,
25
9–2
65
(2
00
9)
Joub
ert
synd
rom
e 2
60
80
91
TMEM
216
Isra
el (
Ash
kena
zi J
ewis
h)Am
. J. H
um. G
enet
. 86,
93
–97
(2
01
0)
Kin
dler
syn
drom
e1
73
65
0FE
RM
T1A
lger
ia, T
unis
iaH
um. M
ol. G
enet
. 12,
92
5–9
35
(2
00
3)
Kra
bbe
dise
ase
24
52
00
GAL
CIs
rael
(P
ales
tini
an)
Am. J
. Hum
Gen
et. 5
3, 1
25
0–1
25
5 (
19
93
)
Kuf
or-R
akeb
syn
drom
e6
06
69
3AT
P13A
2Jo
rdan
Nat
. Gen
et. 3
8, 1
18
4–1
19
1 (
20
06
)
Leth
al c
onge
nita
l con
trac
ture
syn
drom
e 2
60
75
98
ERB
B3
Isra
el (
Bed
ouin
)Am
. J. H
um. G
enet
. 81,
58
9–5
95
(2
00
7)
Leth
al c
onge
nita
l con
trac
tura
l syn
drom
e 3
61
13
69
PIP5
K1C
Isra
el (
Bed
ouin
)Am
. J. H
um. G
enet
. 81,
53
0–5
39
(2
00
7) (c
onti
nued
)
Tabl
e 1
exa
mpl
es o
f ge
nes
for
men
delia
n di
seas
es id
enti
fied
in c
onsa
ngui
neou
s fa
mili
es f
rom
the
med
iter
rane
an r
egio
n (c
onti
nued
)
Dis
ease
ID
fro
m M
ende
lian
Inhe
rita
nce
in M
anO
MIM
#G
ene
Fam
ily o
rigi
nR
efer
ence
Leuk
odys
trop
hy, d
ysm
yelin
atin
g an
d sp
asti
c pa
rapa
resi
s w
ith
or w
itho
ut d
ysto
nia
61
24
43
FA2H
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 83,
64
3–6
48
(2
00
8)
Lipo
dyst
roph
y, c
onge
nita
l gen
eral
ized
, typ
e 2
26
97
00
BSC
L2Le
bano
n, T
urke
yN
at. G
enet
. 28,
36
5–3
70
(2
00
1)
Live
r fa
ilure
, acu
te in
fant
ile6
13
07
0TR
MU
Isra
el (
Yem
enit
e Je
wis
h)Am
. J. H
um. G
enet
. 85,
40
1–4
07
(2
00
9)
Mac
roce
phal
y, a
lope
cia,
cut
is la
xa a
nd s
colio
sis
61
30
75
RIN
2Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et. 8
5, 2
54
–26
3 (
20
09
)
Maj
eed
synd
rom
e6
09
62
8LP
IN2
Jord
anJ.
Med
. Gen
et. 4
2, 5
51
–55
7 (
20
05
)
Mal
de
Mel
eda
24
83
00
SLU
RP1
Alg
eria
, Cro
atia
Hum
. Mol
. Gen
et. 1
0, 8
75
–88
0 (
20
01
)
Mic
roce
phal
ic o
steo
dysp
last
ic p
rim
ordi
al d
war
fism
, typ
e II
21
07
20
PCN
T2Le
bano
nSc
ienc
e 31
9, 8
16
–81
9 (
20
08
)
Mic
roce
phal
y, s
eizu
res
and
deve
lopm
enta
l del
ay6
13
40
2PN
KP
Ital
y, P
ales
tine
, Jor
dan,
Tur
key
Nat
. Gen
et. 4
2, 2
45
–24
9 (
20
10
)
Mit
ocho
ndri
al c
ompl
ex I
V de
fici
ency
22
01
10
FAST
KD
2Is
rael
(B
edou
in)
Am. J
. Hum
. Gen
et. 8
3, 4
15
–42
3 (
20
08
)
Mit
ocho
ndri
al D
NA
dep
leti
on s
yndr
ome,
ene
phal
omyo
path
ic f
orm
wit
h m
ethy
lmal
onic
ac
idur
is, a
utos
omal
rec
essi
ve6
12
07
3SU
CLA2
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 76,
10
81
–10
86
(2
00
5)
Mit
ocho
ndri
al D
NA
dep
leti
on s
yndr
ome,
hep
atoc
ereb
ral f
orm
, aut
osom
al r
eces
sive
25
18
80
DG
UO
KIs
rael
(D
ruze
)N
at. G
enet
. 29,
33
7–3
41
(2
00
1)
Muc
olip
idos
is I
V2
52
65
0M
COLN
1Is
rael
(A
shke
nazi
Jew
ish)
Nat
. Gen
et. 2
6, 1
18
–12
1 (
20
00
)
Mul
tipl
e pt
eryg
ium
syn
drom
e, E
scob
ar v
aria
nt2
65
00
0CH
RN
GLe
bano
n, T
urke
yAm
. J. H
um. G
enet
. 79,
30
3–3
12
(2
00
6)
Myo
glob
inur
ia, a
cute
rec
urre
nt, a
utos
omal
rec
essi
ve2
68
20
0LP
IN1
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 83,
48
9–4
94
(2
00
8)
Neu
rode
gene
rati
on w
ith
brai
n ir
on a
ccum
ulat
ion
2A
25
66
00
PLA2
G6
Isra
el (
Bed
ouin
)Am
. J. H
um. G
enet
. 79,
94
2–9
48
(2
00
6)
Odo
ntoo
nych
oder
mal
dys
plas
ia2
57
98
0W
NT1
0ALe
bano
nAm
. J. H
um. G
enet
. 81,
82
1–8
28
(2
00
7)
Ost
eoge
nesi
s im
perf
ecta
NA
FKB
P65
Turk
eyAm
. J. H
um. G
enet
. 86,
55
1–5
59
(2
01
0)
Pap
illon
-Lef
evre
syn
drom
e2
45
00
0CT
SCE
gypt
, Leb
anon
Nat
. Gen
et. 2
3, 4
21
–42
4 (
19
99
)
Par
ieta
l for
amin
a 2
60
95
97
ALX4
Turk
eyH
um. M
ol. G
enet
. 18,
43
57
–43
66
(2
00
9)
Per
iodo
ntit
is, a
ggre
ssiv
e, 1
17
06
50
CTSC
Jord
an, T
urke
yJ.
Med
. Gen
et. 3
7, 9
5–1
01
(2
00
0)
Pol
ycys
tic
lipom
embr
anou
s os
teod
yspl
asia
wit
h sc
lero
sing
leuk
oenc
epha
lopa
thy
22
17
70
TREM
2Le
bano
nH
um. M
utat
. 29,
E1
94
–E2
04
(2
00
8)
Pol
ymic
rogy
ria,
bila
tera
l fro
ntop
arie
tal
60
68
54
GPR
56Is
rael
(P
ales
tini
an)
Scie
nce
303,
20
33
–20
36
(2
00
4)
Pon
toce
rebe
llar
hypo
plas
ia t
ype
16
07
59
6VR
K1
Isra
el (
Ash
kena
zi J
ewis
h)Am
. J. H
um. G
enet
. 85,
28
1–2
89
(2
00
9)
Pon
toce
rebe
llar
hypo
plas
ia t
ype
66
11
52
3R
ARS2
Isra
el (
Sep
hard
ic J
ewis
h)Am
. J. H
um. G
enet
. 81,
85
7–8
62
(2
00
7)
Pul
mon
ary
alve
olar
mic
rolit
hias
is2
65
10
0SL
C34A
2Tu
rkey
Am. J
. Hum
. Gen
et. 7
9, 6
50
–65
6 (
20
06
)
Seb
orrh
ea-l
ike
derm
atit
is w
ith
psor
iasi
form
ele
men
ts6
10
22
7ZN
F750
Isra
el (
Mor
occa
n Je
wis
h)N
at. G
enet
. 38,
74
9–7
51
(2
00
6)
Sex
rev
ersa
l, fe
mal
e, w
ith
dysg
enes
is o
f ki
dney
s, a
dren
als
and
lung
s6
11
81
2W
NT4
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 82,
39
–47
(2
00
8)
Spl
it-h
and/
foot
mal
form
atio
n 6
22
53
00
WN
T10B
Turk
eyH
um. M
ol. G
enet
. 17,
26
44
–26
53
(2
00
8)
Spo
ndyl
o-m
eta-
epip
hyse
al d
yspl
asia
, sho
rt li
mb-
hand
typ
e2
71
66
5D
DR
2Is
rael
(S
epha
rdic
Jew
ish)
, Pal
esti
neAm
. J. H
um. G
enet
. 84,
80
–84
(2
00
9)
Thre
e M
syn
drom
e 1
27
37
50
CUL7
Fran
ce, I
taly
, Leb
anon
, Por
tuga
lN
at. G
enet
. 37,
11
19
–11
24
(2
00
5)
Tum
oral
cal
cino
sis,
hyp
erph
osph
atem
ic f
amili
al2
11
90
0G
ALN
T3Is
rael
(D
ruze
), P
ales
tine
Nat
. Gen
et. 3
6, 5
79
–58
1 (
20
04
)
Tum
oral
cal
cino
sis,
nor
mop
hosp
hate
mic
fam
ilial
61
04
55
SAM
D9
Isra
el (
Yem
enit
e Je
wis
h)Am
. J. H
um. G
enet
. 79,
75
9–7
64
(2
00
6)
Ush
er s
yndr
ome,
typ
e IG
60
69
43
USH
1GJo
rdan
(P
ales
tini
an)
Hum
. Gen
et. 1
10, 3
48
–35
0 (
20
02
)
Vita
min
E, f
amili
al is
olat
ed d
efic
ienc
y of
27
74
60
TTPA
Fran
ce, I
taly
, Mor
occo
, Tun
isia
Nat
. Gen
et. 9
, 14
1–1
45
(1
99
5)
War
burg
mic
ro s
yndr
ome
60
01
18
RAB
3GAP
Leba
non,
Mor
occo
Nat
. Gen
et. 3
7, 2
21
–22
3 (
20
05
)
Wei
ll-M
arch
esan
i syn
drom
e, a
utos
omal
rec
essi
ve2
77
60
0AD
AMTS
10Le
bano
nAm
. J. H
um. G
enet
. 75,
80
1–8
06
(2
00
4)
Wol
fram
syn
drom
e 2
60
49
28
CISD
2Jo
rdan
Am. J
. Hum
. Gen
et. 8
1, 6
73
–68
3 (
20
07
)
© 2
010
Nat
ure
Am
eric
a, In
c. A
ll ri
gh
ts r
eser
ved
.commentary
nature genetics | volume 42 | number 8 | august 2010 645
Tabl
e 1
exa
mpl
es o
f ge
nes
for
men
delia
n di
seas
es id
enti
fied
in c
onsa
ngui
neou
s fa
mili
es f
rom
the
med
iter
rane
an r
egio
nD
isea
se I
D f
rom
Men
delia
n In
heri
tanc
e in
Man
OM
IM#
Gen
eFa
mily
ori
gin
Ref
eren
ce
Add
ucte
d th
umb-
club
foot
syn
drom
e6
01
77
6CH
ST14
Turk
eyAm
. J. H
um. G
enet
. 85,
87
3–8
82
(2
00
9)
Alo
peci
a, n
euro
logi
c de
fect
s an
d en
docr
inop
athy
61
20
79
RB
M28
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 82,
11
14
–11
21
(2
00
8)
Am
yotr
ophi
c la
tera
l scl
eros
is 2
, juv
enile
20
51
00
ALS2
Tuni
sia
Nat
. Gen
et. 2
9, 1
60
–16
5 (
20
01
)
Ata
xia-
tela
ngie
ctas
ia2
08
90
0AT
MIs
rael
(M
oroc
can
Jew
ish)
Scie
nce
268,
17
49
–17
53
(1
99
5)
Bar
det-
Bie
dl s
yndr
ome
10
20
99
00
BB
S10
Leba
non,
Tur
key
Nat
. Gen
et. 3
8, 5
21
–52
4 (
20
06
)
Bir
k-B
arel
men
tal r
etar
dati
on d
ysm
orph
ism
syn
drom
e6
12
29
2K
CNK
9Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et.
83, 1
93
–19
9 (
20
08
)
Cen
ani s
ynda
ctyl
ism
21
27
80
LRP4
Egy
pt, T
urke
yAm
. J. H
um. G
enet
. 86,
1–1
1 (
20
10
)
Cer
ebel
lar
atax
ia, m
enta
l ret
arda
tion
and
dis
equi
libri
um s
yndr
ome
12
24
05
0VL
DLR
Turk
eyPr
oc. N
atl.
Acad
. Sci
. USA
105
, 42
32
–42
36
(2
00
8)
Cer
ebra
l dys
gene
sis,
neu
ropa
thy,
icht
hyos
is a
nd p
alm
opla
ntar
ker
atod
erm
a sy
ndro
me
60
95
28
SNAP
29Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et. 7
7, 2
42
–25
1 (
20
05
)
Cha
rcot
-Mar
ie-T
ooth
dis
ease
, typ
e 4
H6
09
31
1FG
D4
Alg
eria
, Leb
anon
Am. J
. Hum
. Gen
et. 8
1, 1
–16
(2
00
7)
Cha
rcot
-Mar
ie-T
ooth
dis
ease
, typ
e 4
A2
14
40
0G
DAP
1Tu
nisi
aN
at. G
enet
. 30,
21
–22
(2
00
2)
Cut
is L
axa,
aut
osom
al r
eces
sive
, typ
e II
B6
12
94
0PY
CR1
Ital
y, J
orda
n, P
ales
tine
, Tur
key
Nat
. Gen
et. 4
1, 1
01
6–1
02
1 (
20
09
)
Dyg
gve-
Mel
chio
r-C
laus
en d
isea
se2
23
80
0D
YMLe
bano
n, P
ortu
gal,
Mor
occo
, Tun
isia
J. M
ed. G
enet
. 39,
71
4–7
17
(2
00
2)
Dea
fnes
s, c
onge
nita
l wit
h in
ner
ear
agen
esis
, mic
roti
a an
d m
icro
dont
ia6
10
70
6FG
F3Tu
rkey
Am. J
. Hum
. Gen
et. 8
0, 3
38
–34
4 (
20
07
)
Dea
fnes
s, a
utos
omal
rec
essi
ve 9
, DFN
B9
60
10
71
OTO
FLe
bano
nN
at. G
enet
. 21,
36
3–3
69
(1
99
9)
Dea
fnes
s, a
utos
omal
dom
inan
t 1
5, D
FNA
15
60
24
59
POU
4F3
Isra
el (
Ital
ian
Jew
ish)
Scie
nce
279,
19
50
–19
54
(1
99
8)
Dea
fnes
s, a
utos
omal
rec
essi
ve 2
1, D
FNB
21
60
36
29
TECT
ALe
bano
nH
um. M
ol. G
enet
. 8, 4
09
–41
2 (
19
99
)
Dea
fnes
s, a
utos
omal
rec
essi
ve 2
2, D
FNB
22
60
70
39
OTO
AP
ales
tine
Proc
. Nat
l. Ac
ad. S
ci. U
SA 9
9, 6
24
0–6
24
5 (
20
02
)
Dea
fnes
s, a
utos
omal
rec
essi
ve 2
8, D
FNB
28
60
98
23
TRIO
BP
Pal
esti
neAm
. J. H
um. G
enet
. 78,
14
4–1
52
(2
00
6)
Dea
fnes
s, a
utos
omal
rec
essi
ve 3
0, D
FNB
30
60
71
01
MYO
3AIs
rael
(Ir
aqi J
ewis
h)Pr
oc. N
atl.
Acad
. Sci
. USA
99,
75
18
–75
23
(2
00
2)
Dea
fnes
s, a
utos
omal
rec
essi
ve 3
1, D
FNB
31
60
70
84
WH
RN
Pal
esti
neEu
r. J.
Hum
. Gen
et. 1
0, 2
10
–21
2 (
20
02
)
Dea
fnes
s, a
utos
omal
rec
esiv
e 9
1, D
FNB
91
NA
SER
PIN
B6
Turk
eyAm
. J. H
um. G
enet
. 86,
79
7–8
04
(2
01
0)
Hyp
ertr
ophi
c ne
urop
athy
of
Dej
erin
e-S
otta
s1
45
90
0PR
XLe
bano
nH
um. M
ol. G
enet
. 10,
41
5–4
21
(2
00
1)
Ect
opia
lent
is, i
sola
ted,
aut
osom
al r
eces
sive
22
51
00
ADAM
TSL4
Iraq
, Jor
dan
Am. J
. Hum
. Gen
et. 8
4, 2
74
–27
8 (
20
09
)
Epi
leps
y, p
rogr
essi
ve m
yocl
onic
, 1B
61
24
37
PRIC
KLE
1Is
rael
(P
ales
tini
an),
Jor
dan
Am. J
. Hum
. Gen
et. 8
3, 5
72
–58
1 (
20
08
)
Exo
crin
e pa
ncre
atic
insu
ffic
ienc
y, d
yser
ythr
opoe
itic
ane
mia
and
cal
vari
al h
yper
osto
sis
61
27
14
COX4
I2Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et. 8
4, 4
12
–41
7 (
20
09
)
Fran
k-Te
r H
aar
synd
rom
e2
49
42
0SH
3PXD
2BIs
rael
, Leb
anon
, Tur
key
Am. J
. Hum
. Gen
et. 8
6, 2
54
–26
1 (
20
10
)
Fras
er s
yndr
ome
21
90
00
FRAS
1Fr
ance
, Gre
ece,
Leb
anon
, Spa
inN
at. G
enet
. 34,
20
3–2
08
(2
00
3)
Fron
tona
sal d
yspl
asia
NA
ALX1
Turk
eyAm
. J. H
um. G
enet
. 86,
78
9–7
96
(2
01
0)
H s
yndr
ome
61
23
91
SLC2
9A3
Isra
el (
Pal
esti
nian
), B
ulga
ria
Am. J
. Hum
. Gen
et. 8
3, 5
29
–53
4 (
20
08
)
Hyp
eros
tosi
s-hy
perp
hosp
hate
mia
syn
drom
e6
10
23
3G
ALN
T3Is
rael
(D
ruze
), P
ales
tine
J. M
ol. M
ed. 8
3, 3
3–3
8 (
20
05
)
Hyp
ogon
adot
ropi
c hy
pogo
nadi
sm1
46
11
0TA
C3, T
ACR
3Tu
rkey
Nat
. Gen
et. 4
1, 3
54
–35
8 (
20
09
)
Hyp
otri
chos
is, c
onge
nita
l, w
ith
juve
nile
mac
ular
dys
trop
hy6
01
55
3CD
H3
Isra
el (
Dru
ze)
Nat
. Gen
et. 2
9, 1
34
–13
6 (
20
01
)
Icht
hyos
is, l
amel
lar
36
04
77
7CY
P4F2
2A
lger
ia, F
ranc
e, I
taly
, Leb
anon
Hum
. Mol
. Gen
et. 1
5, 7
67
–77
6 (
20
06
)
Icht
hyos
is w
ith
hypo
tric
hosi
s, a
utos
omal
rec
essi
ve6
10
76
5ST
14Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et. 8
0, 4
67
–47
7 (
20
07
)
Jalil
i syn
drom
e2
17
08
0CN
NM
4K
osov
o, L
eban
onAm
. J. H
um. G
enet
. 84,
25
9–2
65
(2
00
9)
Joub
ert
synd
rom
e 2
60
80
91
TMEM
216
Isra
el (
Ash
kena
zi J
ewis
h)Am
. J. H
um. G
enet
. 86,
93
–97
(2
01
0)
Kin
dler
syn
drom
e1
73
65
0FE
RM
T1A
lger
ia, T
unis
iaH
um. M
ol. G
enet
. 12,
92
5–9
35
(2
00
3)
Kra
bbe
dise
ase
24
52
00
GAL
CIs
rael
(P
ales
tini
an)
Am. J
. Hum
Gen
et. 5
3, 1
25
0–1
25
5 (
19
93
)
Kuf
or-R
akeb
syn
drom
e6
06
69
3AT
P13A
2Jo
rdan
Nat
. Gen
et. 3
8, 1
18
4–1
19
1 (
20
06
)
Leth
al c
onge
nita
l con
trac
ture
syn
drom
e 2
60
75
98
ERB
B3
Isra
el (
Bed
ouin
)Am
. J. H
um. G
enet
. 81,
58
9–5
95
(2
00
7)
Leth
al c
onge
nita
l con
trac
tura
l syn
drom
e 3
61
13
69
PIP5
K1C
Isra
el (
Bed
ouin
)Am
. J. H
um. G
enet
. 81,
53
0–5
39
(2
00
7) (c
onti
nued
)
Tabl
e 1
exa
mpl
es o
f ge
nes
for
men
delia
n di
seas
es id
enti
fied
in c
onsa
ngui
neou
s fa
mili
es f
rom
the
med
iter
rane
an r
egio
n (c
onti
nued
)
Dis
ease
ID
fro
m M
ende
lian
Inhe
rita
nce
in M
anO
MIM
#G
ene
Fam
ily o
rigi
nR
efer
ence
Leuk
odys
trop
hy, d
ysm
yelin
atin
g an
d sp
asti
c pa
rapa
resi
s w
ith
or w
itho
ut d
ysto
nia
61
24
43
FA2H
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 83,
64
3–6
48
(2
00
8)
Lipo
dyst
roph
y, c
onge
nita
l gen
eral
ized
, typ
e 2
26
97
00
BSC
L2Le
bano
n, T
urke
yN
at. G
enet
. 28,
36
5–3
70
(2
00
1)
Live
r fa
ilure
, acu
te in
fant
ile6
13
07
0TR
MU
Isra
el (
Yem
enit
e Je
wis
h)Am
. J. H
um. G
enet
. 85,
40
1–4
07
(2
00
9)
Mac
roce
phal
y, a
lope
cia,
cut
is la
xa a
nd s
colio
sis
61
30
75
RIN
2Is
rael
(P
ales
tini
an)
Am. J
. Hum
. Gen
et. 8
5, 2
54
–26
3 (
20
09
)
Maj
eed
synd
rom
e6
09
62
8LP
IN2
Jord
anJ.
Med
. Gen
et. 4
2, 5
51
–55
7 (
20
05
)
Mal
de
Mel
eda
24
83
00
SLU
RP1
Alg
eria
, Cro
atia
Hum
. Mol
. Gen
et. 1
0, 8
75
–88
0 (
20
01
)
Mic
roce
phal
ic o
steo
dysp
last
ic p
rim
ordi
al d
war
fism
, typ
e II
21
07
20
PCN
T2Le
bano
nSc
ienc
e 31
9, 8
16
–81
9 (
20
08
)
Mic
roce
phal
y, s
eizu
res
and
deve
lopm
enta
l del
ay6
13
40
2PN
KP
Ital
y, P
ales
tine
, Jor
dan,
Tur
key
Nat
. Gen
et. 4
2, 2
45
–24
9 (
20
10
)
Mit
ocho
ndri
al c
ompl
ex I
V de
fici
ency
22
01
10
FAST
KD
2Is
rael
(B
edou
in)
Am. J
. Hum
. Gen
et. 8
3, 4
15
–42
3 (
20
08
)
Mit
ocho
ndri
al D
NA
dep
leti
on s
yndr
ome,
ene
phal
omyo
path
ic f
orm
wit
h m
ethy
lmal
onic
ac
idur
is, a
utos
omal
rec
essi
ve6
12
07
3SU
CLA2
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 76,
10
81
–10
86
(2
00
5)
Mit
ocho
ndri
al D
NA
dep
leti
on s
yndr
ome,
hep
atoc
ereb
ral f
orm
, aut
osom
al r
eces
sive
25
18
80
DG
UO
KIs
rael
(D
ruze
)N
at. G
enet
. 29,
33
7–3
41
(2
00
1)
Muc
olip
idos
is I
V2
52
65
0M
COLN
1Is
rael
(A
shke
nazi
Jew
ish)
Nat
. Gen
et. 2
6, 1
18
–12
1 (
20
00
)
Mul
tipl
e pt
eryg
ium
syn
drom
e, E
scob
ar v
aria
nt2
65
00
0CH
RN
GLe
bano
n, T
urke
yAm
. J. H
um. G
enet
. 79,
30
3–3
12
(2
00
6)
Myo
glob
inur
ia, a
cute
rec
urre
nt, a
utos
omal
rec
essi
ve2
68
20
0LP
IN1
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 83,
48
9–4
94
(2
00
8)
Neu
rode
gene
rati
on w
ith
brai
n ir
on a
ccum
ulat
ion
2A
25
66
00
PLA2
G6
Isra
el (
Bed
ouin
)Am
. J. H
um. G
enet
. 79,
94
2–9
48
(2
00
6)
Odo
ntoo
nych
oder
mal
dys
plas
ia2
57
98
0W
NT1
0ALe
bano
nAm
. J. H
um. G
enet
. 81,
82
1–8
28
(2
00
7)
Ost
eoge
nesi
s im
perf
ecta
NA
FKB
P65
Turk
eyAm
. J. H
um. G
enet
. 86,
55
1–5
59
(2
01
0)
Pap
illon
-Lef
evre
syn
drom
e2
45
00
0CT
SCE
gypt
, Leb
anon
Nat
. Gen
et. 2
3, 4
21
–42
4 (
19
99
)
Par
ieta
l for
amin
a 2
60
95
97
ALX4
Turk
eyH
um. M
ol. G
enet
. 18,
43
57
–43
66
(2
00
9)
Per
iodo
ntit
is, a
ggre
ssiv
e, 1
17
06
50
CTSC
Jord
an, T
urke
yJ.
Med
. Gen
et. 3
7, 9
5–1
01
(2
00
0)
Pol
ycys
tic
lipom
embr
anou
s os
teod
yspl
asia
wit
h sc
lero
sing
leuk
oenc
epha
lopa
thy
22
17
70
TREM
2Le
bano
nH
um. M
utat
. 29,
E1
94
–E2
04
(2
00
8)
Pol
ymic
rogy
ria,
bila
tera
l fro
ntop
arie
tal
60
68
54
GPR
56Is
rael
(P
ales
tini
an)
Scie
nce
303,
20
33
–20
36
(2
00
4)
Pon
toce
rebe
llar
hypo
plas
ia t
ype
16
07
59
6VR
K1
Isra
el (
Ash
kena
zi J
ewis
h)Am
. J. H
um. G
enet
. 85,
28
1–2
89
(2
00
9)
Pon
toce
rebe
llar
hypo
plas
ia t
ype
66
11
52
3R
ARS2
Isra
el (
Sep
hard
ic J
ewis
h)Am
. J. H
um. G
enet
. 81,
85
7–8
62
(2
00
7)
Pul
mon
ary
alve
olar
mic
rolit
hias
is2
65
10
0SL
C34A
2Tu
rkey
Am. J
. Hum
. Gen
et. 7
9, 6
50
–65
6 (
20
06
)
Seb
orrh
ea-l
ike
derm
atit
is w
ith
psor
iasi
form
ele
men
ts6
10
22
7ZN
F750
Isra
el (
Mor
occa
n Je
wis
h)N
at. G
enet
. 38,
74
9–7
51
(2
00
6)
Sex
rev
ersa
l, fe
mal
e, w
ith
dysg
enes
is o
f ki
dney
s, a
dren
als
and
lung
s6
11
81
2W
NT4
Isra
el (
Pal
esti
nian
)Am
. J. H
um. G
enet
. 82,
39
–47
(2
00
8)
Spl
it-h
and/
foot
mal
form
atio
n 6
22
53
00
WN
T10B
Turk
eyH
um. M
ol. G
enet
. 17,
26
44
–26
53
(2
00
8)
Spo
ndyl
o-m
eta-
epip
hyse
al d
yspl
asia
, sho
rt li
mb-
hand
typ
e2
71
66
5D
DR
2Is
rael
(S
epha
rdic
Jew
ish)
, Pal
esti
neAm
. J. H
um. G
enet
. 84,
80
–84
(2
00
9)
Thre
e M
syn
drom
e 1
27
37
50
CUL7
Fran
ce, I
taly
, Leb
anon
, Por
tuga
lN
at. G
enet
. 37,
11
19
–11
24
(2
00
5)
Tum
oral
cal
cino
sis,
hyp
erph
osph
atem
ic f
amili
al2
11
90
0G
ALN
T3Is
rael
(D
ruze
), P
ales
tine
Nat
. Gen
et. 3
6, 5
79
–58
1 (
20
04
)
Tum
oral
cal
cino
sis,
nor
mop
hosp
hate
mic
fam
ilial
61
04
55
SAM
D9
Isra
el (
Yem
enit
e Je
wis
h)Am
. J. H
um. G
enet
. 79,
75
9–7
64
(2
00
6)
Ush
er s
yndr
ome,
typ
e IG
60
69
43
USH
1GJo
rdan
(P
ales
tini
an)
Hum
. Gen
et. 1
10, 3
48
–35
0 (
20
02
)
Vita
min
E, f
amili
al is
olat
ed d
efic
ienc
y of
27
74
60
TTPA
Fran
ce, I
taly
, Mor
occo
, Tun
isia
Nat
. Gen
et. 9
, 14
1–1
45
(1
99
5)
War
burg
mic
ro s
yndr
ome
60
01
18
RAB
3GAP
Leba
non,
Mor
occo
Nat
. Gen
et. 3
7, 2
21
–22
3 (
20
05
)
Wei
ll-M
arch
esan
i syn
drom
e, a
utos
omal
rec
essi
ve2
77
60
0AD
AMTS
10Le
bano
nAm
. J. H
um. G
enet
. 75,
80
1–8
06
(2
00
4)
Wol
fram
syn
drom
e 2
60
49
28
CISD
2Jo
rdan
Am. J
. Hum
. Gen
et. 8
1, 6
73
–68
3 (
20
07
)
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