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

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


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • 14-3-3 Proteins / genetics
  • Adult
  • Aged
  • Alu Elements
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Chromosome Duplication*
  • Chromosomes, Human, Pair 17*
  • DNA Copy Number Variations*
  • Female
  • Genetic Loci
  • Genome, Human*
  • Hand Deformities, Congenital / diagnosis
  • Hand Deformities, Congenital / genetics*
  • Hand Deformities, Congenital / pathology
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Sequence Alignment
  • Sequence Analysis, DNA


  • 14-3-3 Proteins
  • BHLHA9 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • YWHAE protein, human