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Hum Mutat. 2016 Feb;37(2):160-4. doi: 10.1002/humu.22929. Epub 2015 Dec 2.

Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.

Author information

1
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
2
Clinical Genetic Service, Department of Health, Hong Kong, China.
3
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.
4
Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
5
Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
6
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030.
8
Texas Children's Hospital, Houston, Texas, 77030.

Abstract

Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density microarray and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus, and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal nonallelic homologous recombination to generate the quadruplications in this family.

KEYWORDS:

Alu repetitive elements; complex genomic rearrangement; digital droplet PCR; quadruplication; split-hand malformation

PMID:
26549411
PMCID:
PMC4718869
DOI:
10.1002/humu.22929
[Indexed for MEDLINE]
Free PMC Article

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