SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease

J Neurol. 2012 Mar;259(3):515-23. doi: 10.1007/s00415-011-6213-8. Epub 2011 Sep 4.

Abstract

Considerable non-allelic heterogeneity for autosomal recessively inherited Charcot-Marie-Tooth (ARCMT) disease has challenged molecular testing and often requires a large amount of work in terms of DNA sequencing and data interpretation or remains unpractical. This study tested the value of SNP array-based whole-genome homozygosity mapping as a first step in the molecular genetic diagnosis of sporadic or ARCMT in patients from inbred families or outbred populations with the ancestors originating from the same geographic area. Using 10 K 2.0 and 250 K Nsp Affymetrix SNP arrays, 15 (63%) of 24 CMT patients received an accurate genetic diagnosis. We used our Java-based script eHoPASA CMT-easy Homozygosity Profiling of SNP arrays for CMT patients to display the location of homozygous regions and their extent of marker count and base-pairs throughout the whole genome. CMT4C was the most common genetic subtype with mutations detected in SH3TC2, one (p.E632Kfs13X) appearing to be a novel founder mutation. A sporadic patient with severe CMT was homozygous for the c.250G > C (p.G84R) HSPB1 mutation which has previously been reported to cause autosomal dominant dHMN. Two distantly related CMT1 patients with early disease onset were found to carry a novel homozygous mutation in MFN2 (p.N131S). We conclude that SNP array-based homozygosity mapping is a fast, powerful, and economic tool to guide molecular genetic testing in ARCMT and in selected sporadic CMT patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Charcot-Marie-Tooth Disease / diagnosis*
  • Charcot-Marie-Tooth Disease / genetics
  • Child
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Female
  • GTP Phosphohydrolases / genetics*
  • Gene Expression Profiling
  • Genetic Predisposition to Disease*
  • Genotype
  • HSP27 Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Molecular Chaperones
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide*
  • Proteins / genetics*
  • Young Adult

Substances

  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Proteins
  • SH3TC2 protein, human
  • GTP Phosphohydrolases
  • MFN2 protein, human