Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing

Abstract

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes, ARHGEF10, POLG, SETX, and SOD1. Eleven families (14%) carried the PMP22 duplication and one family carried a MPZ duplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.

Figure 1

Identified variants in 81 Norwegian CMT families from the general population. Our previous studies identified copy-number variations in 12 CMT families and pathogenic point mutations in 10 CMT families [2, 14, 19]. The remaining 59 CMT families were investigated by next-generation sequencing.

Figure 2

Frequencies of certain and likely pathogenic variants in CMT1 and CMT2 families from the Norwegian general population.

Figure 3

Frequencies of CMT1 and CMT2 point mutation in five studies [9, 10, 12, 13]. Numbers from our study include certainly and likely pathogenic variants, whereas the families with variants of uncertain pathogenicity have been included in the no cause detected group. Patients with intermediate forms of CMT were excluded in our study and the British and American studies but not in the Spanish and Japanese studies as intermediate forms were not differentiated; this may lead to a screw comparison. Numbers from the British study include only patients seen in their inherited neuropathy clinic and numbers from the American study include those with reported neurophysiology.