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Mechanisms for the Generation of Two Quadruplications Associated with Split‐Hand Malformation
Author(s) -
Gu Shen,
Posey Jennifer E.,
Yuan Bo,
Carvalho Claudia M.B.,
Luk H.M.,
Erikson Kelly,
Lo Ivan F.M.,
Leung Gordon K.C.,
Pickering Curtis R.,
Chung Brian H.Y.,
Lupski James R.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22929
Subject(s) - biology , alu element , breakpoint , copy number variation , genetics , germline , microarray , homologous recombination , fetus , comparative genomic hybridization , chromosomal translocation , gene , chromosome , human genome , genome , pregnancy , gene expression
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.