Novel copy-number variants in a population-based investigation of classic heterotaxy

Shannon L Rigler; Denise M Kay; Robert J Sicko; Ruzong Fan; Aiyi Liu; Michele Caggana; Marilyn L Browne; Charlotte M Druschel; Paul A Romitti; Lawrence C Brody; James L Mills

doi:10.1038/gim.2014.112

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Novel copy-number variants in a population-based investigation of classic heterotaxy

Journal article

Open access

Peer reviewed

Novel copy-number variants in a population-based investigation of classic heterotaxy

Shannon L Rigler, Denise M Kay, Robert J Sicko, Ruzong Fan, Aiyi Liu, Michele Caggana, Marilyn L Browne, Charlotte M Druschel, Paul A Romitti, Lawrence C Brody, …

Genetics in medicine, Vol.17(5), pp.348-357

05/2015

DOI: 10.1038/gim.2014.112

PMCID: PMC5901701

PMID: 25232849

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Abstract

Heterotaxy is a clinically and genetically heterogeneous disorder. We investigated whether screening cases restricted to a classic phenotype would result in the discovery of novel, potentially causal copy-number variants. We identified 77 cases of classic heterotaxy from all live births in New York State during 1998-2005. DNA extracted from each infant's newborn dried blood spot was genotyped with a microarray containing 2.5 million single-nucleotide polymorphisms. Copy-number variants were identified with PennCNV and cnvPartition software. Candidates were selected for follow-up if they were absent in unaffected controls, contained 10 or more consecutive probes, and had minimal overlap with variants published in the Database of Genomic Variants. We identified 20 rare copy-number variants including a deletion of BMP2, which has been linked to laterality disorders in mice but not previously reported in humans. We also identified a large, terminal deletion of 10q and a microdeletion at 1q23.1 involving the MNDA gene; both are rare variants suspected to be associated with heterotaxy. Our findings implicate rare copy-number variants in classic heterotaxy and highlight several candidate gene regions for further investigation. We also demonstrate the efficacy of copy-number variant genotyping in blood spots using microarrays.

Sequence Deletion

Congenital Abnormalities - epidemiology

Genetic Association Studies

Humans

Risk Factors

Genotype

Infant

Male

Case-Control Studies

DNA Copy Number Variations

Congenital Abnormalities - diagnosis

Phenotype

Congenital Abnormalities - genetics

Comparative Genomic Hybridization

Female

Polymorphism, Single Nucleotide

New York - epidemiology

Population Surveillance

Infant, Newborn

Details

Title: Subtitle: Novel copy-number variants in a population-based investigation of classic heterotaxy
Creators: Shannon L Rigler - 1] Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA Department of Neonatology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
Denise M Kay - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA
Robert J Sicko - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA
Ruzong Fan - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
Aiyi Liu - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
Michele Caggana - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA
Marilyn L Browne - 1] Congenital Malformations Registry, New York State Department of Health, Albany, New York, USA Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA
Charlotte M Druschel - 1] Congenital Malformations Registry, New York State Department of Health, Albany, New York, USA Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Rensselaer, New York, USA
Paul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, Iowa, USA
Lawrence C Brody - Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
James L Mills - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
Resource Type: Journal article
Publication Details: Genetics in medicine, Vol.17(5), pp.348-357
Publisher: United States
DOI: 10.1038/gim.2014.112
PMID: 25232849
PMCID: PMC5901701
ISSN: 1098-3600
eISSN: 1530-0366
Grant note: U01 DD000492 / NCBDD CDC HHS Wellcome Trust HHSN275201100001C / NICHD NIH HHS HHSN275201100001I / NICHD NIH HHS HHSN27500005 / PHS HHS HHSN275201100001G / NICHD NIH HHS U01 DD001035 / NCBDD CDC HHS N01DK73431 / NICHD NIH HHS N01-DK-73431 / NIDDK NIH HHS
Language: English
Date published: 05/2015
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9983995004202771

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