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

TitleMechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.
Publication TypeJournal Article
Year of Publication2016
AuthorsGu, S, Posey, JE, Yuan, B, Carvalho, CMB, Luk, HM, Erikson, K, Lo, IFM, Leung, GKC, Pickering, CR, H Y Chung, B, Lupski, JR
JournalHum Mutat
Date Published2016 Feb
Keywords14-3-3 Proteins, Adult, Aged, Alu Elements, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Chromosome Duplication, Chromosomes, Human, Pair 17, DNA Copy Number Variations, Female, Genetic Loci, Genome, Human, Hand Deformities, Congenital, Humans, Infant, Male, Molecular Sequence Data, Pedigree, Sequence Alignment, Sequence Analysis, DNA

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.

Alternate JournalHum Mutat
PubMed ID26549411
PubMed Central IDPMC4718869
Grant ListR01GM106373 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
T32 GM07526 / GM / NIGMS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States

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