Inheritance of Charcot–Marie–Tooth disease 1A with rare nonrecurrent genomic rearrangement

Abstract

Rare copy number variations by the nonrecurrent rearrangements involving PMP22 have been recently suggested to be associated with CMT1A peripheral neuropathy. As a mechanism of the nonrecurrent rearrangement, replication-based fork stalling template switching (FoSTeS) by microhomology-mediated break-induced replication (MMBIR) has been proposed. We found three Korean CMT1A families with putative nonrecurrent duplication. The duplications were identified by microsatellite typing and applying a CGH microarray. The breakpoint sequences in two families suggested an Alu-Alu-mediated rearrangement with the FoSTeS by the MMBIR, and a two-step rearrangement of the replication-based FoSTeS/MMBIR and meiosis-based recombination. The two-step mechanism has still not been reported. Segregation analysis of 17p12 microsatellite markers and breakpoint junction analysis suggested that the nonrecurrent rearrangements are stably inherited without alteration of junction sequence; however, they may allow some alteration of the genomic contents in duplication across generations by recombination event. It might be the first study on the pedigree analysis of the large CMT1A families with nonrecurrent rearrangements. It seems that the exact mechanism of the nonrecurrent rearrangements in the CMT1A may have a far more complex process than has been expected.

Wide phenotypic variations in Charcot-Marie-Tooth 1A neuropathy with rare copy number variations on 17p12

“…We identified three unique CNVs associated with nonrecurrent rearrangements on 17p12 from three CMT1A families: two simple duplications and a complex duplication (Choi et al 2011). Although nonrecurrent genomic rearrangements have been reported recently in the CMT1A or HNPP patients, this study might be the first full clinical examination study.…”

“…They were from three Korean CMT1A families (FC85, FC116 and FC388) with rare CNV on 17p12 by nonrecurrent rearrangement (Choi et al 2011). All participants in this study provided written informed consent.…”

“…We previously reported three CMT1A families with rare CNVs by nonrecurrent rearrangements on chromosome 17p12 by the haplotyping of microsatellites and aCGH application (Choi et al 2011). The FC116 and FC388 families showed a single duplication, whereas the FC85 family showed a complex rearrangement with two discrete regions ( Table 1).…”

“…According to the FoSTeS/MMBIR model, the active replication fork could stall and switch templates via complementary template microhomology to anneal and prime DNA replication. Although the common NAHR mechanism is a prevalent underlying cause of CMT1A, rare CNVs by nonrecurrent rearrangements have been also reported to be associated with the CMT1A and HNPP (Zhang et al 2009;Zhang et al 2010;Huang et al 2010;Choi et al 2011). …”

“…We previously identified three CMT1A families with partial duplication by nonrecurrent rearrangements in Korean CMT families (Choi et al 2011). The detailed clinical phenotypes have still not been reported in CMT1A with rare CNVs on 17p12.…”