Journal
JOURNAL OF NEUROLOGY
Volume 259, Issue 3, Pages 515-523Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00415-011-6213-8
Keywords
Autosomal recessive CMT; Homozygosity mapping; SNP array; Hereditary neuropathies; Gene
Categories
Funding
- Austrian Science Fond (FWF) [P19455-B05]
- Land Steiermark (GZ) [A3-12G 114-06/1]
- Oesterreichische Nationalbank (ONB [13010]
- Austrian Science Fund (FWF) [P19455] Funding Source: Austrian Science Fund (FWF)
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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.
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