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

Eur J Med Genet. May-Jun 2011;54(3):214-9. doi: 10.1016/j.ejmg.2010.12.003. Epub 2010 Dec 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Base Sequence
  • Blotting, Western
  • Calpain / genetics
  • Calpain / metabolism
  • Caveolin 3 / genetics
  • Caveolin 3 / metabolism
  • Child
  • Chromosome Mapping
  • Consanguinity
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Genome, Human / genetics*
  • Genome-Wide Association Study / methods*
  • Genotype
  • Homozygote
  • Humans
  • Male
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscular Dystrophies, Limb-Girdle / diagnosis
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Muscular Dystrophies, Limb-Girdle / metabolism
  • Mutation
  • Pedigree
  • Pentosyltransferases
  • Polymorphism, Single Nucleotide*
  • Proteins / genetics

Substances

  • Caveolin 3
  • Muscle Proteins
  • Proteins
  • FKRP protein, human
  • Pentosyltransferases
  • CAPN3 protein, human
  • Calpain

Supplementary concepts

  • Limb-girdle muscular dystrophy type 2A

Associated data

  • RefSeq/NM_000070
  • RefSeq/NM_024344
  • RefSeq/NM_173087
  • RefSeq/NM_173088
  • RefSeq/NM_173089
  • RefSeq/NM_173090
  • RefSeq/NM_212465
  • RefSeq/NM_212467