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

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.

SUBMITTER: Papic L

PROVIDER: S-EPMC3085821 | biostudies-literature | 2011 May-Jun

REPOSITORIES: biostudies-literature

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

Papić Lea L Fischer Dirk D Trajanoski Slave S Höftberger Romana R Fischer Carina C Ströbel Thomas T Schmidt Wolfgang M WM Bittner Reginald E RE Schabhüttl Maria M Gruber Karin K Pieber Thomas R TR Janecke Andreas R AR Auer-Grumbach Michaela M

European journal of medical genetics 20101221 3

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 ...[more]

PMID: 21172462

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Dataset Information

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

Publications

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

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