2009 Vienna - European Society of Human Genetics

Molecular basis of Mendelian disorders
Conclusion: The most frequent genes implicated in autosomal recessive
nonsyndromic hearing loss are GJB2, which is responsible for
more than half of cases.In our study, there was a significant relationship
between consanguineous marriage in our evaluated group and
express of NSHl (PV#0/00 and O.R= 3.43). but there was not any significant
relationship between inheritance pattern and consanguineous
marriage with 35delG mutation. These data can help genetic counselor
and otolaryngologist for setting priority in evaluation, prevention
and even treatment in these patients.
P12.124
De novo mutations in stXBP1 cause early infantile epileptic
encephalopathy
N. Matsumoto, H. Saitsu;
Yokohama City University, Yokohama, Japan.
Early infantile epileptic encephalopathy with suppression-burst (EIEE),
also known as Ohtahara syndrome, is one of the most severe and
earliest forms of epilepsy. Using array-based comparative genomic
hybridization (aCGH), we found a de novo 2.0-Mb microdeletion at
9q33.3-q34.11 in a female EIEE patient. Mutation analysis of candidate
genes mapped to the deletion revealed that four unrelated EIEE
patients had heterozygous missense mutations in syntaxin binding
protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally
conserved neuronal Sec1/Munc-18 (SM) protein, which plays
an essential role for synaptic vesicle release in multiple species. Circular
dichroism (CD) melting experiments revealed that a mutant protein
was significantly thermolabile compared to the wild type. Furthermore,
binding of the mutant protein to syntaxin was impaired. These findings
suggest that haploinsufficiency of STXBP1 causes EIEE. Following
doctors are highly appreciated: Drs. Mitsuhiro Kato (Yamagata
University School of Medicine), Hitoshi Osaka (Kanagawa Children’s
Medical Center), Jun Tohyama (Nishi-Niigata Chuo National Hospital),
Katsuhisa Uruno (NHO Yamagata National Hospital), Satoko Kumada
(Tokyo Metropolitan Neurological Hospital).
P12.125
New mutations in the CXORF5 (OFD1) gene and the influence
of X-inactivation on the phenotype in patients with type i
Orofaciodigital syndrome
I. J. Bisschoff, C. Zeschnigk, G. Wolff, D. J. Morris-Rosendahl;
Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany.
Thirteen forms of Orofaciodigital Syndrome (OFDS) have been described,
however CXORF5 (Xp22.3-p22.2) is currently the only known
causative gene, in which mutations cause OFD type I (OFD1). OFD1 is
characterized by malformations of the face, oral cavity, and digits and
is transmitted as an X-linked dominant condition with lethality in males.
There may be central nervous system involvement in as many as 40%
of cases, and polycystic kidney disease seems to be specific to OFD1.
We have performed mutation analysis via DNA sequencing in 27 sporadic
and two familial cases of suspected OFD1. Fourteen mutations,
nine of which have not previously been described, were found in the index
patients. Five of the mutations (36%) are predicted to affect splicing.
Mental retardation has previously been associated with mutations
in CXORF5 exons 3, 8, 9, 13 and 16. We have found a new splice
mutation in intron 1, c.13-10T>A, in a mother and her two daughters,
with greatly diverging phenotypes, especially with regard to cognitive
ability. X-inactivation studies in lymphocytes showed preferential inactivation
of the mutation allele in the mildly affected mother (normal
intelligence) and relatively mildly affected daughter, whereas both alleles
appeared to be equally active in the severely retarded daughter.
Reverse transcription PCR and sequencing in lymphocytes revealed
the markedly increased presence of an extra, larger transcript which
includes intron 1, in the most severely affected daughter. Our results
suggest that the pattern of X inactivation has a greater effect on the
brain phenotype than the type of mutation.
P12.126
mutational spectrum of the cOL1A1 and cOL1A2 genes in
spanish patients with Osteogenesis imperfecta
J. Garcia-Planells, M. Molero, M. Lazaro, M. Torres-Puente, M. Perez-Alonso;
Medical Genetics Unit. Sistemas Genomicos, Valencia, Spain.
Osteogenesis Imperfecta (OI) is a group of disorders characterized
by bones that break easily. Clinical features are very heterogeneous
and up to seven clinical types have been described. OI is predominantly
inherited in an autosomal dominant manner although recessive
forms have been described. Dominant forms are caused by mutations
in either COL1A1 or COL1A2 genes, located on 17q21-22 and 7q22
chromosomal regions respectively. In this work we report our results
and experience in the genetic diagnosis of Osteogenesis Imperfecta
in a wide cohort of patients coming from several Spanish hospitals.
Mutational analysis of both COL1A1 and COL1A2 genes has been
performed by double-strand sequencing. Results are discussed on the
basis of inter and intragenic mutational distribution, type of mutation,
aminoacid residues, familial implications and genotype-phenotype
correlations. We highlight the elevated percentage of mutations not
previously reported (more than 50%) identified in our population. A
high expertise and experience must be required for the interpretation
of nucleotide changes identified in genes with a high rate of de novo
and novel (not yet reported) mutations, especially, in paediatric patients
because potential social and legal implications and patients with
a reproductive interest. Mutational spectrum of COL1A1 and COL1A2
genes depicted in our population provides an interesting epidemiologic
and pathogenic information about Osteogenesis Imperfecta.
P12.127
Distinct Oi Phenotype caused by cOL1 c-proteinase site
mutations
A. M. Barnes 1 , K. Lindahl 2 , T. Hefferan 3 , C. Rubin 2 , A. Kindmark 2 , M. Whyte 4 , W.
McAlister 4 , S. Mumm 4 , A. Boskey 5 , O. Ljunggren 2 , J. C. Marini 1 ;
1 BEMB, NICHD/NIH, Bethesda, MD, United States, 2 Uppsala University, Uppsala,
Sweden, 3 Mayo Clinic, Rochester, MN, United States, 4 Shriner’s Hospital
for Children, St. Louis, MO, United States, 5 Weill Medical College, New York,
NY, United States.
Osteogenesis imperfecta (OI) is often caused by mutations in the type
I collagen genes. Mutations in the type I procollagen C-propeptide
cleavage site are of interest because they disrupt a processing step.
We identified two children with mild OI who had cleavage site mutations
in COL1A1 (P1: α1(I)D1041N) or COL1A2 (P2: α2(I)A1029T). P1
DEXA z-score and pQCT vBMD were +3, contrasting with radiographs
demonstrating osteopenia and os-in-os vertebrae, and histomorphometry
revealing increased bone remodeling, without a mineralization
defect or signs of osteosclerosis. P2 had a DEXA z-score of 0, gracile
long bones with radiographic osteopenia, and decreased BV/TV and
increased BFR without a mineralization defect on histomorphometry.
FTIR imaging analysis in both cortical and trabecular bone confirms
that P1 and P2 have elevated mineral/matrix and collagen maturity
compared to age-matched controls or a proband with classical OI.
Steady-state collagen electrophoresis showed slight overmodification
of α1(I) and α2(I) in cell layers of both probands, with a slight baseline
delay in P1. Chain incorporation was normal in P1 and slightly
delayed in P2. Pericellular processing of P1 was delayed, with increases
in both pCα1 and proα2, while P2 had increased pCα2 and
proα2 and normal processing kinetics. Together with an adult with an
α1(I)A1040T substitution (Int Conn Tis 82S1: CC01), our cases suggest
that defects in proα1(I) processing lead to high childhood BMD
possibly due to increased bone mineral content, with signs of osteopetrosis
occurring subsequently. Proα1(I) cleavage appears crucial to Cpropeptide
processing, while defective proα2(I) cleavage occurs after
α1(I) processing.
P12.128
Pelizaeus-merzbacher Disease - different molecular defects
result in various clinical picture?
D. Hoffman-Zacharska1 , M. Nawara1 , K. Poirier2 , H. Mierzewska1 , T. Mazurczak1
, J. Poznanski3 , A. Kierdaszuk4 , J. Madry5 , J. Chelly6 , J. Bal1 ;
1 2 Institute of Mother and Child, Warsaw, Poland, Universite Paris Desceartes;
Institut Cochin: INSERM Unite, Paris, France, 3Institute of Biochemistry and
Biophysics, Warsaw, Poland, 4Provincial Hospital, Biala Podlaska, Poland,
5 6 Medical University, Warsaw, Poland, Universite Paris Desceartes; Institut
Cochin: INSERM Unite, Warsaw, Poland.
Pelizaeus-Merzbacher disease (PMD; OMIM 312080) is a rare, severe
dysmyelination brain disorder caused by mutation in the X-linked gene
PLP1. PMD typically manifests in infancy or early childhood with nystagmus,
hypotonia, and cognitive impairment; the findings progress
to severe spasticity and ataxia; life span is shortened. PLP1 protein
is exceptionally well-conserved in mammals showing nearly no poly-