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Am J Hum Genet. 2014 Mar 6;94(3):462-9. doi: 10.1016/j.ajhg.2014.01.017. Epub 2014 Feb 13.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
3
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel; Sacker Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
4
Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
5
Quest Diagnostics Inc., Athena Diagnostics, Worcester, MA 01605, USA.
6
Department of Neurology, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University, Nashville, TN 37232, USA.
7
Department of Neurology, Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232, USA.
8
Sacker Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics and Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.

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.

PMID:
24530202
PMCID:
PMC3951935
DOI:
10.1016/j.ajhg.2014.01.017
[Indexed for MEDLINE]
Free PMC Article

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