title: Copy number variants in a population-based investigation of Klippel-Trenaunay syndrome.
abstract: Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular disorder that is thought to occur sporadically; however, reports of familial occurrence suggest a genetic component. We examined KTS cases to identify novel, potentially causal copy number variants (CNVs). We identified 17 KTS cases from all live-births occurring in New York (1998-2010). Extracted DNA was genotyped using Illumina microarrays and CNVs were called using PennCNV software. CNVs selected for follow-up had ≥10 single nucleotide polymorphisms (SNPs) and minimal overlap with in-house controls or controls from the Database of Genomic Variants. We identified 15 candidate CNVs in seven cases; among them a deletion in two cases within transcripts of HDAC9, a histone deacetylase essential for angiogenic sprouting of endothelial cells. One of them also had a duplication upstream of SALL3, a transcription factor essential for embryonic development that inhibits DNMT3A, a DNA methyltransferase responsible for embryonic de novo DNA methylation. Another case had a duplication spanning ING5, a histone acetylation regulator active during embryogenesis. We identified rare genetic variants related to chromatin modification which may have a key role in regulating vascular development during embryogenesis. Further investigation of their implications in the pathogenesis of KTS is warranted. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Dimopoulos
authors.affiliation: Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sicko
authors.affiliation: Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kay
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rigler
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ruzong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Romitti
authors.affiliation: Congenital Malformations Registry, New York State Department of Health, Albany, New York.|Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York.
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Browne
authors.affiliation: Congenital Malformations Registry, New York State Department of Health, Albany, New York.|Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Druschel
authors.affiliation: Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York.
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D007715:Klippel-Trenaunay-Weber Syndrome / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D008423:Maternal Age; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D015995:Prevalence; D012042:Registries; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D012097:Repressor Proteins; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords:  HDAC9; DNMT3A; ING5; Klippel-Trenaunay syndrome; SALL3; angiogenesis; chromatin modification; copy number variant