Inheritance of CMT disease 1A with rare nonrecurrent genomic rearrangement

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Neurogenetics. 2010 Dec 31

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

rearrangement.

Choi BO, Kim NK, Park SW, Hyun YS, Jeon HJ, Hwang JH, Chung KW.

Department of Neurology, School of Medicine, Ewha Womans University, Seoul,

South Korea.

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.