A comprehensive molecular genetic workup for autosomal recessive forms of CMT

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A comprehensive molecular genetic workup for autosomal recessive forms of

CharcotMarie-Tooth disease.

C. Stendel\ A. Roos2

, E. Battaloglu3

, J. Clayton-Srnith4

, P. De Jonghe5

, S. Erdem6

, A.

Gabreels-Festen7

, A. Hahn8

, W. Miiller-Felber9

, Y. Parman10

, V. Plante-Bordeneuvel1

,

B. Rautenstrauss12

, J. M. Schriider13

, V. Straubl 4, Y. Takiyamal5

, V. Timmermans, H.

Topaloglul6

, A. Urtizberea17

, S. Ziichnerl8

, J. Weis13

, K. Zerres2 and.T. Senderek1

,2

'Institute of Cell Biology, ETH Zurich, Zurich, Switzerland; 'Institute of Human

Genetics, Aachen University

of Technology, Aachen, Germany; 'Department of Molecular Biology and Genetics,

Bogazi,i University, Istanbul, Turkey; 4Academic Unit of Medical Genetics, St

's Hospital, Manchester, UK; 'Department of

Molecular Genetics, Flanders Interuniversity Institute for Biotechnology,

University of Antwerp, Antwerp,Belgium; 'Department of Neurology and

Neuromuscular Diseases Research laboratory, Hacettepe University, Ankara,

Turkey; 'Institute of Neurology, University Medical Center St Radboud, Nijmegen,

The Netherlands;

'Department of Neuropediatrics, Justus-Liebig-University, Giessen, Germany;

'Friedrich-Baur-Institute, Department of Neurology,

Ludwig-Maximilian-University, Munich, Germany; " 'Neurology Department,

Istanbul Faculty of Medicine, Istanbul, Turkey; " Hopital de BicStre, Service de

Neurologie, Paris, France; " Department of Human Genetics, Friedrich-

University, Erlangen-Niirnberg, Germany; " Institute of Neuropathology, Aachen

University of Technology, Aachen, Germany; '4Institute of Human Genetics,

Newcastle University, Newcastle upon Tyne, UK; " Division of Neurology,

Department ofInternal Medicine,

Jichi Medical University, Tochigi, Japan; " Department of Pediatric Neurology,

Hacettepe Children's Hospital, Ankara, Turkey; I'Hopital Marin de Hendaye,

Hendaye, France; " Miami Institute for Human Genomics, School of Medicine,

University of Miami, Miami, USA

Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) account for

less than 5 % of the CMT families in Westem countries. However, in communities

with a high proportion of consanguineous marriages, ARCMT constitutes 30-50 % of

cases ARCMT is

genetically heterogeneous with more than a dozen known genes and loci. The

identification of an ever increasing number of genes associated with ARCMT

requires an economicstrategy to characterize the gene defects in families

affected with the disease.

We performed a systematic genetic screening of 90 ARCMT families by a

combination of linkage analysis, homozygosity mapping and sequencing. Genotyping

of polymorphic markers for 14 ARCMT loci reduced the number of genes to be

sequenced to one or two candidates in 60 % of the families. Subsequent mutation

analysis allowed the identification of disease causing mutations in GDAPl,

MIMR2, SBF2 (MIMR13), KlAA1985 (SH3IC2), NDRGl, PRX, and FGD4 KlAA1985 (SH3 I

C2) mutations were by far the most frequent identified cause of ARCMT in our

cohort.

Overall, we determined the genetic defect in 34 families, giving a

mutation detection rate of 38 %. Our strategy appears to be an efficient and

effective means for gene-based molecular diagnosis of ARCMT.