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Charcot-Marie-Tooth disease (CMT) is an umbrella term for more than 90 different genetic causes of inherited peripheral neuropathies (http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/) and has an estimated prevalence of 1 in 2500. Most cases present within the first two decades of life but increasing axonal genetic subtypes (CMT2) first present in adulthood. Identifying additional genes causing CMT2 is important because these can identify molecular pathways involved in axonal degeneration and enable development of rational therapies for these and related disorders.
We have used whole exome sequencing (WES) to identify two families with CMT2 caused by mutations in the Bcl2-associated athanogene 3 (BAG3). Mutations in BAG3 have previously been shown to cause a myofibrillar myopathy1 2 often associated with cardiomyopathy that usually presents in childhood. Children have been reported with peripheral neuropathy in addition to myopathy3 and/or cardiomyopathy.4
Genomic analysis was focused on rare and conserved variants that followed an autosomal-dominant inheritance pattern in WES of both probands using the GEM.app/GENESIS software. We only considered variants that met the following criteria: (1) non-synonymous change; (2) minor allele frequency in Exome Aggregation Consortium (ExAC) database <0.0001 out of ~120 000 chromosomes; (3) not present in more than two families within the GEM.app/GENESIS database of 12 500 chromosomes; 4)Genomic Evolutionary Rate Profiling (GERP) >3 or PhastCons >0.6; and (5) genotype quality >75. This analysis resulted in the identification of a variant in BAG3 (c.625C>T; p.Pro209Ser) that completely cosegregated with the presence of neuropathy in both large families (figure 1 …