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SNP-array based whole genome homozygosity mapping : a quick and powerful tool to achieve an accurate diagnosis in LGMD2 patients

Papi?, Lea and Fischer, Dirk and Trajanoski, Slave and Höftberger, Romana and Fischer, Carina and Ströbel, Thomas and Schmidt, Wolfgang M. and Bittner, Reginald E. and Schabhüttl, Maria and Gruber, Karin and Pieber, Thomas R. and Janecke, Andreas R. and Auer-Grumbach, Michaela. (2011) SNP-array based whole genome homozygosity mapping : a quick and powerful tool to achieve an accurate diagnosis in LGMD2 patients. European journal of medical genetics, Vol. 54, H. 3. pp. 214-219.

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Official URL: http://edoc.unibas.ch/dok/A6003464

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Abstract

A large number of novel disease genes have been identified by homozygosity mapping and the positional candidate approach. In this study we used single nucleotide polymorphism (SNP) array-based, whole genome homozygosity mapping as the first step to a molecular diagnosis in the highly heterogeneous muscle disease, limb girdle muscular dystrophy (LGMD). In a consanguineous family, both affected siblings showed homozygous blocks on chromosome 15 corresponding to the LGMD2A locus. Direct sequencing of CAPN3, encoding calpain-3, identified a homozygous deletion c.483delG (p.Ile162SerfsX17). In a sporadic LGMD patient complete absence of caveolin-3 on Western blot was observed. However, a mutation in CAV3 could not be detected. Homozygosity mapping revealed a large homozygous block at the LGMD2I locus, and direct sequencing of FKRP encoding fukutin-related-protein detected the common homozygous c.826 C<A (p.Leu276Ile) mutation. Subsequent re-examination of this patient's muscle biopsy showed aberrant ?-dystroglycan glycosylation. In summary, we show that whole-genome homozygosity mapping using low cost SNP arrays provides a fast and non-invasive method to identify disease-causing mutations in sporadic patients or sibs from consanguineous families in LGMD2. Furthermore, this is the first study describing that in addition to PTRF, encoding polymerase I and transcript release factor, FKRP mutations may cause secondary caveolin-3 deficiency.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Neuro- und Entwicklungspädiatrie (Weber)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Neuro- und Entwicklungspädiatrie (Weber)
UniBasel Contributors:Fischer, Dirk
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:1769-7212
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:25 Oct 2013 08:32
Deposited On:25 Oct 2013 08:32

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