title: 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 α-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.
authors.affiliation: Department of Internal Medicine, Division of Diabetes and Metabolism, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
authors.forename: Lea
authors.initials: L
authors.lastname: Papić
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
authors.forename: Slave
authors.initials: S
authors.lastname: Trajanoski
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.forename: Carina
authors.initials: C
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Schmidt
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
authors.forename: Maria
authors.initials: M
authors.lastname: Schabhüttl
authors.forename: Karin
authors.initials: K
authors.lastname: Gruber
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D002648:Child; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010430:Pentosyltransferases; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics
chemical_list: D051244:Caveolin 3; D009124:Muscle Proteins; D011506:Proteins; C443107:FKRP protein, human; D010430:Pentosyltransferases; C105884:CAPN3 protein, human; D002154:Calpain