Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication.

Abstract

Copy-number variations cause genomic disorders. Triplications, unlike deletions and duplications, are poorly understood because of challenges in molecular identification, the choice of a proper model system for study, and awareness of their phenotypic consequences. We investigated the genomic disorder Charcot-Marie-Tooth disease type 1A (CMT1A), a dominant peripheral neuropathy caused by a 1.4 Mb recurrent duplication occurring by nonallelic homologous recombination. We identified CMT1A triplications in families in which the duplication segregates. The triplications arose de novo from maternally transmitted duplications and caused a more severe distal symmetric polyneuropathy phenotype. The recombination that generated the triplication occurred between sister chromatids on the duplication-bearing chromosome and could accompany gene conversions with the homologous chromosome. Diagnostic testing for CMT1A (n = 20,661 individuals) identified 13% (n = 2,752 individuals) with duplication and 0.024% (n = 5 individuals) with segmental tetrasomy, suggesting that triplications emerge from duplications at a rate as high as ~1:550, which is more frequent than the rate of de novo duplication. We propose that individuals with duplications are predisposed to acquiring triplications and that the population prevalence of triplication is underascertained.

• Authors: Pengfei Liu, Violet Gelowani, Feng Zhang, Vivian E Drory, Shay Ben-Shachar, Erin Roney, Adam C Medeiros, Rebecca J Moore, Christina DiVincenzo, William B Burnette, Joseph J Higgins, Jun Li, Avi Orr-Urtreger, James R Lupski
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 94 Issue 3 Pg. 462-9 (Mar 06 2014) ISSN: 1537-6605 [Electronic] United States
• PMID: 24530202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Topics

• Alleles
• Charcot-Marie-Tooth Disease (epidemiology, genetics, physiopathology)
• DNA Copy Number Variations
• Female
• Gene Dosage
• Gene Duplication
• Humans
• Male
• Microsatellite Repeats
• Muscular Atrophy (pathology)
• Nucleic Acid Hybridization
• Pedigree
• Phenotype
• Polyneuropathies (genetics)
• Recombination, Genetic