2009 Vienna - European Society of Human Genetics

Concurrent Sessions
abnormal glycosylation of α-dystroglycan in muscle. Only a portion
of the patients present with mental retardation (MR), with or without
structural brain and ocular malformations. These disorders are caused
by mutations in at least six genes encoding O-mannosyltransferases
(POMT1 and POMT2), O-mannosyl N-acetylglucosaminyltransferase1
(POMGNT1), and enzymes of unknown function (FKRP, LARGE and
FKTN).
The most frequently mutated gene is FKRP, associated with a large
spectrum of phenotypes varying from mild LGMD2I often due to the
founder mutation, L276I, to the most severe form of the spectrum
with major structural brain and eye malformations and early lethality,
called Walker Warburg syndrome (WWS). We studied a large cohort
of muscular dystrophy patients with histological and clinical features of
α-dystroglycanopathy and identified mutations in all 6 genes, including
founder mutations in FKRP and POMT2, and large genomic rearrangements
in POMT2 and LARGE.
From genotype-phenotype analysis of 26 CMD families with alpha-dystroglycan
hypoglycosylation and POMGNT1 (3), POMT1 (4), POMT2
(10), FKTN (3), and LARGE (1) mutations, we suggest the screening
of POMT1 and POMT2 first in CMD patients with MR, especially if
there is microcephaly, cerebellar hypoplasia, white matter abnormalities
or cortical dysplasia, even in the absence of eye involvement. In
CMD or LGMD patients with normal intellectual development, other
genes are better candidates (FKRP, FKTN) , especially if there is progressive
cardiac dysfunction.
c14.3
mutations of LRTOMT, a fusion gene with alternative reading
frames, cause autosomal recessive nonsyndromic hearing
impairment in DFNB families.
E. Kalay 1,2 , S. Masmoudi 3 , Z. M. Ahmed 4 , I. A. Belyantseva 4 , M. A. Mosrati 3 , R.
W. J. Collin 2,5 , S. Riazuddin 4 , M. Hmani-Aifa 3 , H. Venselaar 6 , M. N. Kawar 4 , A.
Tlili 3 , B. van der Zwaag 7 , S. Y. Khan 8 , L. Ayadi 3 , R. J. Morell 4 , A. J. Griffith 9 , I.
Charfedine 10 , R. Caylan 11 , J. Oostrik 2 , A. Karaguzel 1 , A. Ghorbel 10 , S. Riazuddin
8 , T. B. Friedman 4 , H. Ayadi 3 , H. Kremer 5,12 ;
1 Department of Medical Biology, Faculty of Medicine, Karadeniz Technical
University, Trabzon, 61080, Turkey, 2 Department of Human Genetics, Radboud
University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands,
3 Unite´ Cibles pour le Diagnostic et la The´rapie, Centre de Biotechnologie, de
Sfax, 3018, Tunisia, 4 Laboratory of Molecular Genetics, National Institute on
Deafness and Other Communication Disorders, Rockville, MD, United States,
5 Department of Otorhinolaryngology, Radboud University Nijmegen Medical
Centre, Nijmegen 6500 HB, The Netherlands, 6 Center for Molecular and
Biomolecular Informatics, Radboud University Nijmegen, Nijmegen 6500 HB,
The Netherlands, 7 Department of Neuroscience and Pharmacology, Rudolf
Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht
3584 CG, The Netherlands, 8 National Center of Excellence in Molecular Biology,
University of the Punjab, Lahore 53700, Pakistan, 9 Otolaryngology Branch,
National Institute on Deafness and Other Communication Disorders, Rockville,
MD, United States, 10 Service d’O.R.L, C.H.U. Habib Bourguiba, de Sfax, 3029,
Tunisia, 11 Department of Otorhinolaryngology, Faculty of Medicine, Karadeniz
Technical University, Trabzon, 61080, Turkey, 12 Nijmegen Centre for Molecular
Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud
University Nijmegen, Nijmegen, The Netherlands.
Hereditary hearing impairment is a genetically heterogeneous disorder.
Identification of the causative deafness genes is a considerable strategy
to uncover the molecular basis of hearing. Reassessment of three
DFNB63 families which were used in the identification of the DFNB63
locus and two additional Tunisian families helped to narrow the critical
DFNB63 region to a 1.03 Mb interval. This interval has 26 annotated
and predicted genes and sequencing of these genes revealed four
pathogenic mutations in an uncharacterized gene LRRC51, renamed
LRTOMT. LRTOMT has two alternative reading frames and encodes
two different proteins LRTOMT1 and LRTOMT2. LRTOMT2 is a putative
methyltransferase. Further characterization showed that in the
primate lineage, LRTOMT evolved from the fusion of two neighboring
ancestral genes. In rodents, there are two separate genes, designated
Lrrc51 and Tomt which together are orthologous to the primate
LRTOMT. RT-PCR analysis of human tissues showed that LRTOMT
is widely expressed. RNA in situ hybridization in mouse revealed the
expression of Tomt in the cochlear and vestibular sensory cells of the
developing inner ear. Immunolocalization studies of Lrrc51 and Tomt
in the P30 mouse inner ear showed the expression of both genes in
vestibular and cochlear hair cells and their supporting cells. Our data
indicates that LRTOMT is essential for hearing and the identification of
LRTOMT, which encodes a leucine-rich protein and a methyltransferase,
opens an exciting new field for genetic and physiological studies
of the inner ear and hearing.
c14.4
clinical and mutational spectrum of the Legius syndrome (or
NF1-like syndrome)
L. M. Messiaen 1 , S. Yao 1 , H. Brems 2 , T. Callens 1 , E. Denayer 2 , P. Arn 3 , D.
Babovic-Vuksanovic 4 , C. Bay 5 , L. Escobar 6 , R. Greenstein 7 , R. Hachen 8 , M.
Irons 9 , E. Lemire 10 , K. Leppig 11 , M. McDonald 12 , V. Narayanan 13 , L. R. Shapiro 14 ,
D. Tegay 15 , E. Zackai 8 , K. Taniguchi 16 , T. Ayada 16 , A. Yoshimura 16 , A. Parret 17 , B.
Korf 1 , E. Legius 2 ;
1 UAB Medical Genomics Laboratory, Birmingham, AL, United States, 2 KUL
Menselijke Erfelijkheid, Leuven, Belgium, 3 Nemours Children’s clinic, Jacksonville,
FL, United States, 4 Mayo Clinic, Rochester, MN, United States, 5 University
of Kentucky, Lexinton, KY, United States, 6 Medical Genetics, Indianapolis, IN,
United States, 7 University of Connecticut, West Hartford, CT, United States,
8 University of Pennsylvania School of Medicine, Philadelphia, PA, United
States, 9 Children’s Hospital Boston, Boston, MA, United States, 10 University of
Saskatchewan, Saskatoon, SK, Canada, 11 University of Washington, Seattle,
WA, United States, 12 Duke University Medical Center, Durham, NC, United
States, 13 Genetics and Child Neurology, Phoenix, AZ, United States, 14 Sound
Shore Children’s Medical Group, Hawthorne, NJ, United States, 15 New York
College of Osteopathic Medicine, Old Westbury, NY, United States, 16 Kyushu
University, Fukuoka, Japan, 17 EMBL, Heidelberg, Germany.
Autosomal dominant inactivating SPRED1 mutations have recently
been described in 5 families with a neurofibromatis type 1-like syndrome
(NFLS). The phenotype consists of café-au-lait-macules
(CALM), axillary freckling and macrocephaly. The full clinical spectrum
of this new disorder has not yet been investigated.
We performed SPRED1 mutation analysis in 1318 unrelated patients
presenting with a broad range of signs typically found in neurofibromatosis
type 1 (NF1) and in whom no NF1 mutation was present in
peripheral blood lymphocytes. A comparison between clinical findings
in patients with a SPRED1 mutation versus those with a NF1 mutation
and those without known mutation was made. Functional assays were
used to evaluate the pathogenicity of identified missense mutations.
We identified 34 different SPRED1 mutations in 43 probands: twenty
seven were pathogenic (including 2 missense mutations) and 7 missense
mutations were classified as probably benign. Forty eight percent
of SPRED1-positive patients fulfilled NIH NF1 diagnostic criteria
based on the presence of >5 CALM +/- freckling or a NF1-compatible
family history. We estimate that 1.2-2.9% of individuals with the clinical
diagnosis of NF1 have NFLS.
A high SPRED1 mutation detection rate was found in NF1 mutationnegative
families with an autosomal dominant phenotype with CALM
+/- freckling and no other NF1 features. The NF1 diagnostic criteria
are not specific, since 48% of patients with NFLS fulfilled these criteria.
NFLS is not associated with the high incidence of peripheral and central
nervous system tumors seen in NF1. We suggest a less intensive
medical follow-up program for patients with NFLS.
c14.5
three subgroups of neurodegeneration with brain iron
accumulation (NBiA)
M. Hempel1 , H. Prokisch1,2 , T. Kmiec3 , E. Jurkiewicz3 , T. Meitinger1,2 , M. B.
Hartig1 ;
1 2 Institute of Human Genetics, Munich, Germany, Helmholtz Zentrum München,
Munich, Germany, 3Memorial Children’s Health Institute, Warsaw, Poland.
Objective: Neurodegeneration with brain iron accumulation (NBIA) is
a heterogeneous group of disorders characterized by iron deposits in
the basal ganglia. Mutations in two different genes can be responsible
for NBIA: PANK2 gene and PLA2G6 gene. A third gene was discovered
recently by our laboratory. From the clinical point of view all NBIA
patients share common symptoms. Nevertheless we suppose these
patients can be distinguished in three clinical subgroups. Because of
small patient numbers analysis of clinical symptoms is difficult.
Methods: We present a structured clinical evaluation of a large collection
of NBIA patients characterized by one clinician (n=49). A mutation
analysis of the PANK2 gene has been done in all patients. Patients