title: Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.
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.
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Clinical Genetic Service, Department of Health, Hong Kong, China.
authors.forename: H M
authors.initials: HM
authors.lastname: Luk
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Kelly
authors.initials: K
authors.lastname: Erikson
authors.affiliation: Clinical Genetic Service, Department of Health, Hong Kong, China.
authors.forename: Ivan F M
authors.initials: IF
authors.lastname: Lo
authors.affiliation: Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Gordon K C
authors.initials: GK
authors.lastname: Leung
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.affiliation: Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Brian H Y
authors.initials: BH
authors.lastname: Chung
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030.|Texas Children's Hospital, Houston, Texas, 77030.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics; D000328:Adult; D000368:Aged; D020087:Alu Elements; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D058674:Chromosome Duplication; D002886:Chromosomes, Human, Pair 17; D056915:DNA Copy Number Variations; D005260:Female; D056426:Genetic Loci; D015894:Genome, Human; D006228:Hand Deformities, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D048948:14-3-3 Proteins; D051792:Basic Helix-Loop-Helix Proteins; C571985:BHLHA9 protein, human; C482983:YWHAE protein, human
keywords: Alu repetitive elements; complex genomic rearrangement; digital droplet PCR; quadruplication; split-hand malformation