2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
an autosomal recessive form of the disease (LCCS2, MIM 607598)
in Israeli Bedouin kindred to chromosome 12q13 . We now mapped
a similar phenotype (LCCS3) in another Bedouin kindred to 3 .4Mb
on chromosome 19p13, demonstrating a homozygous mutation in
PIP5K1C, encoding phosphatidylinositol-4-phosphate 5-kinase, type I,
gamma (PIPKIγ), an enzyme that phophorylates phosphatidylinositol
4-phosphate (PI4P) to generate phosphatidylinositol-4,5-bisphosphate
(PIP2) . The mutation abolishes the kinase activity of PIP5K1C . Based
on this finding, we sequenced genes in the LCCS2 locus that encode
proteins in pathways interacting with the phosphatidylinositol pathway .
We demonstrate that LCCS2 is caused by a mutation in ERBB3 (Her3)
which is known to modulate PI3K, an enzyme that phosphorylates
PIP2 to produce phosphatidylinositol-3,4,5-triphosphate (PIP3) . Thus,
a defect in the phosphatidylinositol pathway leading to decrease in
synthesis of PIP2, a molecule active in endocytosis of synaptic vesicle
proteins, culminates in lethal congenital arthrogryposis .
c03.5
Drastic reduction in the life span of cystatin c L68Q gene
carriers due to life-style changes in the last two centuries
A. Palsdottir 1 , A. Helgason 2,3 , S. Palsson 4,5 , H. T. Bjornsson 6 , B. T. Bragason 1 ,
S. Gretarsdottir 2 , U. Thorsteinsdottir 2,7 , E. Olafsson 8,7 , K. Stefansson 2,7 ;
1 Institute for Experimental Pathology, Keldur, University of Iceland, Reykjavík,
Iceland, 2 DeCODE Genetics, Reykjavík, Iceland, 3 Department of Anthropology,
University of Iceland, Reykjavik, Iceland, 4 Institute of Biology, University
of Iceland, Reykjavík, Iceland, 5 DeCODE Genetics, Reykjavik, Iceland, 6 Johns
Hopkins University School of Medicine, Baltimore, MD, United States, 7 Faculty
of Medicine, University of Iceland, Reykjavik, Iceland, 8 Department of Neurology,
LSH University Hospital, Reykjavík, Iceland.
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal
dominant disease with high penetrance, manifest by brain hemorrhages
in young normotensive adults . In Iceland, this condition is caused
by the L68Q mutation in the cystatin C gene, leading to amyloid deposition
in cerebral arterioles, ending in the death of contemporary carriers
at an average age of only 30 years . Here, we report, based both
on linkage disequilibrium and genealogical evidence, that all known
copies of this mutation derive from a common ancestor born roughly
18 generations ago . Intriguingly, the genealogies reveal that obligate
L68Q carriers, in all families, born 1825 to 1900 experienced a drastic
reduction in life span, from 65 years to the present day average . At
the same time, a parent-of-origin effect emerged, whereby maternal
inheritance of the mutation was associated with a 9 year reduction
in life span relative to paternal inheritance . As these trends can be
observed in several different extended families, three centuries after
the mutational event, it seems likely that some environmental factor
is responsible, perhaps linked to radical changes in the life-style of
Icelanders during this period . A mutation with such radically different
phenotypic effects in reaction to normal variation in human life-style
not only opens the possibility of preventive strategies for HCCAA, it
may also provide novel insights into the complex relationship between
genotype and environment in human disease .
c03.6
Greater than 1% of contemporary West Africans are carriers of a
Founder mutation for severe Recessive type Viii Oi, Which Was
Presumably Brought to America with the colonial slave trade
and Also Occurs in African-Americans
W. A. Cabral 1 , A. M. Barnes 1 , C. N. Rotimi 2 , L. Brody 3 , J. E. Bailey-Wilson 4 , F.
D. Porter 5 , J. C. Marini 1 ;
1 Bone & Extracellular Matrix Branch, NICHD, NIH, Bethesda, MD, United
States, 2 National Human Genome Center, Howard University, Washington, DC,
United States, 3 Molecular Pathogenesis Section, Genome Technology Branch,
NHGRI, NIH, Bethesda, MD, United States, 4 Statistical Genetics Section, Inherited
Disease Research Branch, NHGRI, NIH, Baltimore, MD, United States,
5 Heritable Disorders Branch, NICHD, NIH, Bethesda, MD, United States.
Classical Osteogenesis imperfecta (OI) is caused by a wide variety
of dominant mutations, many de novo, in type I collagen and has an
incidence of 1/20,000 births . Two recessive OI types, caused by defects
in cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1
(LEPRE1), account for approximately 5% of OI cases in North America.
We identified a recurring mutation in LEPRE1, IVS5+1G>T (Nat
Genet (2007) 39:359-365) in 6 probands (9/12 alleles) with severe/lethal
recessive type VIII OI (OMIM #610915) . All probands had carrier
parents who were African-Americans or contemporary West-African
immigrants to USA, suggesting the existence of a mutant allele which
had been transported to America with the colonial slave trade . To estimate
the carrier frequency of IVS5+1G>T in African-Americans, we
extracted genomic DNA from 1429 random African-American newborn
metabolic screening cards from Pennsylvania. We identified 1/286
carriers (0 .35%), predicting a possible incidence of lethal type VIII
OI due to IVS5+1G>T homozygosity of 1/330,000 African-American
births . Furthermore, genomic DNA from contemporary West Africans
was screened by SNP assay, followed by PCR confirmation of positive
samples . Fifteen of 1097 independent individuals (1 .37%) from Nigeria
and Ghana were heterozygous for IVS5+1G>T . This high carrier
frequency suggests that the incidence of type VIII OI in West Africa
from this mutation alone is equivalent to the incidence of dominant OI .
Haplotype data on probands, carriers and unaffected sibs supports the
occurrence of a common founder mutation over 300 years ago, consistent
with our hypothesis on the transportation of this West African
allele to the Americas .
c04.1
copy number variations in patients with overgrowth syndromes
detected by array-cGH
V. Malan 1,2 , V. Cormier-Daire 1,2 , S. Chevallier 1 , C. Coubes 3 , D. Lacombe 4 , L.
Pasquier 5 , J. Soulier 6 , N. Morichon-Delvallez 1,2 , M. Vekemans 1,2 , A. Munnich 1,2 ,
L. Colleaux 1,2 ;
1 Departement de Génétique et INSERM U781, Paris, France, 2 Université
Paris Descartes, Paris, France, 3 CHU Hôpital Saint-Eloi, Montpellier, France,
4 Service de Génétique Médicale, Centre Hospitalier Universitaire Pellegrin,
Bordeaux, France, 5 Unité de Génétique Clinique, Hôpital Sud, Rennes, France,
6 Laboratoire d’Hématologie, Hôpital Saint-Louis, Paris, France.
Overgrowth syndromes are a heterogeneous group of conditions including
endocrine hormone disorders, several genetic syndromes and
many situations with thus far unexplained mechanisms . Interestingly,
chromosomal deletions and duplications have been identified in patients
with overgrowth such as dup(4)(p16 .3), dup(15)(q26-qter) and
del(9)(q22 .32-q22 .33) . Thus, we hypothesized that the sensitivity of
array-CGH could improve the genetic diagnosis of overgrowth conditions
.
Sixty-five patients with unexplained overgrowth syndrome were analyzed
using a 1 Mb resolution array-CGH. The patients were classified
into two groups: group I (32 cases) includes patients with a clinically
known syndrome (i .e Sotos syndrome or Simpson-Golabi-Behmel syndrome)
whereas group II (32 cases) includes patients with unclassified
overgrowth syndrome .
We detected eight possibly pathogenic imbalances (12,3%) among 2
patients belonging to group I and 6 patients belonging to group II . Two
are deletions and 6 are duplications . No recurrent abnormality was
identified. FISH analyses confirmed the chromosomal abnormalities in
5 cases while the remaining cases are still under investigation .
Firstly, these results demonstrate that array-CGH is able to provide a
high diagnostic yield in patients with overgrowth syndrome . Secondly,
while chromosomal deletions are most often associated with growth
retardation, we found that the majority of the imbalances detected in
our patients are duplications . Thirdly, careful re-examination of patients
may allow the delineation of novel clinically recognizable overgrowth
syndromes .Finally, besides their importance for diagnosis and genetic
counseling, these data may pave the way to the search of genes involved
in the pathogenesis of overgrowth .
c04.2
Design, implementation and results using diagnostic oligo arraycgh
J. A. Crolla1,2 , S. Huang2 , S. J. Beal2 , V. Maloney2 , J. C. K. Barber2 ;
1 2 University of Southampton, Salisbury, United Kingdom, National Genetics
Reference Laboratory (Wessex), Salisbury, United Kingdom.
Array-cgh is an essential tool for the detection, quantification and interpretation
of cryptic copy number changes throughout the genome . Using
Agilent Technology’s eARRAY we have designed and customised a
60mer oligo array printed in 4x44K format (i .e . four 44,000 oligo arrays
per slide) . This constitutional array provides maximum even coverage
of the genome and targets known microdeletion/duplication syndrome
regions, is semi-automatable and provides a high-throughput platform
for array-cgh . To date we have reported 350 diagnostic oligo arrays
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