Efficient identification of novel mutations in patients with limb girdle muscular dystrophy.

Neurogenetics
Steven E BoydenPeter B Kang

Abstract

Limb girdle muscular dystrophy type 2 (LGMD2) is a genetically heterogeneous autosomal recessive disorder caused by mutations in 15 known genes. DNA sequencing of all candidate genes can be expensive and laborious, whereas a selective sequencing approach often fails to provide a molecular diagnosis. We aimed to efficiently identify pathogenic mutations via homozygosity mapping in a population in which the genetics of LGMD2 has not been well characterized. Thirteen consanguineous families containing a proband with LGMD2 were recruited from Saudi Arabia, and for 11 of these families, selected individuals were genotyped at 10,204 single nucleotide polymorphisms. Linkage analysis excluded all but one or two known genes in ten of 11 genotyped families, and haplotype comparisons between families allowed further reduction in the number of candidate genes that were screened. Mutations were identified by DNA sequencing in all 13 families, including five novel mutations in four genes, by sequencing at most two genes per family. One family was reclassified as having a different myopathy based on genetic and clinical data after linkage analysis excluded all known LGMD2 genes. LGMD2 subtypes A and B were notably absent from our sample of pa...Continue Reading

References

Dec 4, 2001·Nature Genetics·Gonçalo R AbecasisLon R Cardon
Aug 31, 2002·Nucleic Acids Research·Vasily RamenskyShamil Sunyaev
Jul 9, 2004·Human Molecular Genetics·Stephen J SawcerJonathan L Haines
Sep 28, 2007·Neuromuscular Disorders : NMD·Harriet P LoKathryn N North
Sep 5, 2008·Current Opinion in Neurology·Michela GuglieriHanns Lochmüller
May 26, 2009·Nucleic Acids Research·Dominik SeelowPeter Nürnberg
May 29, 2009·Clinical Genetics·A T J M Helderman-van den EndenE Bakker
Oct 3, 2009·Journal of Medical Genetics·H M HarvilleF Hildebrandt

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Citations

Apr 25, 2012·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Perrine CastetsValérie Allamand
Jun 7, 2012·Nucleic Acids Research·Dominik Seelow, Markus Schuelke
Aug 10, 2011·Current Opinion in Neurology·Vincenzo NigroGiulio Piluso
Aug 21, 2012·American Journal of Medical Genetics. Part a·Mohammed Al-OwainZuhair Al-Hassnan
Oct 17, 2013·Neuromuscular Disorders : NMD·Satomi MitsuhashiPeter B Kang

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Methods Mentioned

BETA
biopsy
genotyping
PCR

Software Mentioned

ClustalW
PolyPhen
MERLIN
Affymetrix
SeqScape

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