The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy

Abstract

Purpose Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology. Methods Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs. Results Putatively causative CNVs were identified in five subjects (~2.5%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals. Conclusion Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.

Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3

“…The reciprocal 1.5 Mb 17p12 deletion causes hereditary neuropathy with liability to pressure palsies (HNPP) [ 18 ]. Although relatively rare [ 19 – 21 ], a small number of individual cases describing whole and partial gene duplications or deletions for other CMT loci including MPZ [ 21 – 23 ], GJB1 [ 24 – 26 ], MFN2 [ 27 ], and NDRG1 [ 28 ] have also been reported. Currently there are no interchromosomal insertions reported as a cause of CMT.…”

Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis

“…Secondly, in addition to the copy number variations (CNVs) of PMP22 , we did not detect any further CNVs in other causative genes. Although CNVs outside of PMP22 locus are rare, it is still important to test them in CMT cases negative for the PMP22 duplication [ 33 – 35 ]. Finally, there are still many other CMT causative-genes that remain to be identified.…”

Copy Number Variations in Amyotrophic Lateral Sclerosis: Piecing the Mosaic Tiles Together through a Systems Biology Approach

“…While the majority represents benign polymorphic variants, increasing numbers of CNVs are associated with a higher risk of developing various types of inherited Mendelian and complex disease traits, including neurological disorders [ 29 , 30 ]. Several recent studies, in fact, have supported the role of CNVs in causing or influencing the susceptibility to many neurological and developmental conditions, such as Charcot–Marie–Tooth neuropathy [ 31 ], autism [ 32 ], schizophrenia [ 33 ], epilepsy [ 34 ], Crohn’s disease [ 35 ], and neurodegenerative disorders, including Alzheimer’s, Parkinson’s and ALS [ 36 , 37 ].…”