title: SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease.
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.
authors: Center for Medical Research, Medical University of Graz, Graz, Austria.
authors: Carina
authors: C
authors: Fischer
authors: Slave
authors: S
authors: Trajanoski
authors: Lea
authors: L
authors: Papić
authors: Christian
authors: C
authors: Windpassinger
authors: Günther
authors: G
authors: Bernert
authors: Michael
authors: M
authors: Freilinger
authors: Maria
authors: M
authors: Schabhüttl
authors: Mine
authors: M
authors: Arslan-Kirchner
authors: Poupak
authors: P
authors: Javaher-Haghighi
authors: Barbara
authors: B
authors: Plecko
authors: Jan
authors: J
authors: Senderek
authors: Christian
authors: C
authors: Rauscher
authors: Wolfgang N
authors: WN
authors: Löscher
authors: Thomas R
authors: TR
authors: Pieber
authors: Andreas R
authors: AR
authors: Janecke
authors: Michaela
authors: M
authors: Auer-Grumbach
mesh_terms: D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; C488620:SH3TC2 protein, human; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human