Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis
Abstract
The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.
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The atrial septal defects due to Ccn1 haploinsufficiency resemble those observed in some human patients with mutations in AVSD1, a susceptibility locus for non-syndromic AVSD identified by linkage analysis.
“The atrial septal defects due to Ccn1 haploinsufficiency resemble those observed in some human patients with mutations in AVSD1, a susceptibility locus for non-syndromic AVSD identified by linkage analysis.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [97]
The human CCN1 gene and AVSD1 both map within the same chromosomal location at 1p21-31, suggesting that CCN1 may be a candidate gene for human AVSD.
“The human CCN1 gene and AVSD1 both map within the same chromosomal location at 1p21–31 [97,98], suggesting that CCN1 may be a candidate gene for human AVSD.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [97]
Human AVSD is a common group of congenital disorders often associated with Down syndrome, whereas non-syndromic AVSDs are typically inherited with autosomal dominance.
“Human AVSD is a common group of congenital disorders often associated with Down’s syndrome, whereas non-syndromic AVSDs are typically inherited with autosomal dominance [97].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [97]
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- Authors
- Sheffield, V.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Sheffield, V.
- ORCID
- Sheffield, V.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-01-01
- Volume
- 6
- Issue
- 1
- Pages
- 117-121
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2124687151
- Cited by
- 86
- References
- 31
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 1 · 2012: 5
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (2p50hg000835-05, 5p50hl042266-09, 5r01hg000457-06)
- National Heart, Lung, and Blood Institute (HL 42266)
- National Human Genome Research Institute (HG00457, P50HG00835)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
- Keywords
- congenital heart disease, atrioventricular septal defect, non-syndromic congenital heart disease, genetic susceptibility loci, chromosome 1, autosomal dominant inheritance, incomplete penetrance, DNA pooling, multifactorial inheritance
- MeSH terms
- Chromosome Mapping, DNA, Endocardial Cushion Defects, Female, Humans, Male, Pedigree, Genetic Predisposition to Disease
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