Charcot-Marie-Tooth disease (CMT): statistical analysis and revision of molecular genetic diagnostics in a patient population and identification of the disease locus in a large Norwegian family with CMT.

Abstract

CMT is a common inherited disease of the peripheral nerves that may be caused by mutations in multiple genes, most are rare. Our aim was to describe the spectrum of mutations and genes in Norwegian CMT patients, identify factors associated with diagnostic findings, revise the testprotocol, and evaluate the assessments of genetic variants of uncertain clinical significance. Furthermore, we searched to identify the disease associated gene in a large family with a CMT2-like-disorder. We evaluated the data given in laboratory request forms accompanying 559 samples sent for CMT testing during a seven year period. Diagnostic testing was in compliance with recommended algorithms. In paper I we suggest a simplified algorithm intended for diagnostic CMT testing in referral laboratories. Segregation analysis of twenty-two relatives (9 affected) from eight families led to the reclassification of four sequence variants of uncertain clinical significance (paper II). The results of paper II demonstrate the importance of precise clinical data, particularly when investigating variants of uncertain clinical significance. In paper III we performed whole genome linkage analysis, haplotype analysis, SOD1 sequencing and clinical and neurophysiological investigations in a large kindred with a CMT2-like-disorder. The mutation c.140A>G, p.His47Arg in SOD1 segregated with the disease. The results of paper III illustrate the complex genetic etiology of lower motor neuron disease, and identify a common cause of CMT2-like disease in Norway.