title: Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities.
abstract: Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. seemal@bcm.tmc.edu
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.forename: Chad
authors.initials: C
authors.lastname: Shaw
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Lance W
authors.initials: LW
authors.lastname: Patterson
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kolodziejska
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.forename: Zhishuo
authors.initials: Z
authors.lastname: Ou
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.forename: Sung-Hae L
authors.initials: SH
authors.lastname: Kang
authors.forename: Amina
authors.initials: A
authors.lastname: Jinnah
authors.forename: Sophia
authors.initials: S
authors.lastname: Ali
authors.forename: Aamir
authors.initials: A
authors.lastname: Malik
authors.forename: Patricia
authors.initials: P
authors.lastname: Hixson
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.forename: Fatima M
authors.initials: FM
authors.lastname: Boricha
authors.forename: Runako
authors.initials: R
authors.lastname: Whittaker
authors.forename: Chumei
authors.initials: C
authors.lastname: Li
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Penny
authors.forename: John Lynn
authors.initials: JL
authors.lastname: Jefferies
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
mesh_terms: D000782:Aneuploidy; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D025063:Chromosome Disorders / Q000235:genetics* / Q000503:physiopathology; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005124:Eye Abnormalities; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics; D017384:Sequence Deletion