Autosomal dominant inheritance of left ventricular outflow tract obstruction

Wessels, Marjolein; Berger, Rudolphus; Frohn-Mulder, Ingrid M.E.; Roos‐Hesselink, Jolien W.; Hoogeboom, Jeanette J.M.; Mancini, Grazia S; Bartelings, Margot M.; Krijger, Ronald R. de; Wladimiroff, J. W.; Niermeijer, Martinus F.; Grossfeld, Paul; Willems, Patrick J.

doi:10.1002/ajmg.a.30601

Cited by 71 publications

(42 citation statements)

References 75 publications

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“…While there is substantial evidence for the underlying genetic contribution to HLHS, and left ventricular outflow tract obstructive defects (LVOTO) [53][54][55][56][57], only a few genes have been identified as important contributors [58,59]. Several studies have investigated the potential role of CNVs in the pathogenicity of HLHS.…”

Section: Hypoplastic Left Heart Syndrome and Other Left-sided Cardiacmentioning

confidence: 99%

Copy Number Variation in Congenital Heart Defects

Lander

Ware

2014

Curr Genet Med Rep

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Section: Hypoplastic Left Heart Syndrome and Other Left-sided Cardiacmentioning

confidence: 99%

Copy Number Variation in Congenital Heart Defects

Lander

Ware

2014

Curr Genet Med Rep

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“…On the basis of large multiplex families with BAV, autosomal dominant inheritance with reduced penetrance has been proposed, [15][16][17] but only 2 genes, KCNJ2 18 and NOTCH1, 19 that account for <5% of BAV cases have been identified. Reasons to explain this apparent lack of success include that there are many genes involved in cardiac valve development (genetic heterogeneity), a focus on protein-changing variants in known candidate genes, and mounting evidence that BAV exhibits complex inheritance (ie, may not be because of a single genetic variant).…”

Section: Clinical Perspective On P 683mentioning

confidence: 99%

Whole Exome Sequencing for Familial Bicuspid Aortic Valve Identifies Putative Variants

Martin

Pilipenko

Kaufman

et al. 2014

Circ Cardiovasc Genet

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Background-Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation. Although highly heritable, few causal variants have been identified. The purpose of this study was to identify genetic variants underlying BAV by whole exome sequencing a multiplex BAV kindred. Methods and Results-Whole exome sequencing was performed on 17 individuals from a single family (BAV=3; other cardiovascular malformation, 3). Postvariant calling error control metrics were established after examining the relationship between Mendelian inheritance error rate and coverage, quality score, and call rate. To determine the most effective approach to identifying susceptibility variants from among 54 674 variants passing error control metrics, we evaluated 3 variant selection strategies frequently used in whole exome sequencing studies plus extended family linkage.No putative rare, high-effect variants were identified in all affected but no unaffected individuals. Eight high-effect variants were identified by ≥2 of the commonly used selection strategies; however, these were either common in the general population (>10%) or present in the majority of the unaffected family members. However, using extended family linkage, 3 synonymous variants were identified; all 3 variants were identified by at least one other strategy. Conclusions-These results suggest that traditional whole exome sequencing approaches, which assume causal variants alter coding sense, may be insufficient for BAV and other complex traits. Identification of disease-associated variants is facilitated by the use of segregation within families. (Circ Cardiovasc Genet. 2014;7:677-683.)

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“…Sporadically it is associated with William Beuren syndrome or Noonan syndrome. Furthermore, there are family clusters with a high prevalence of different left heart obstructive defects including CoA, bicuspid aortic valve, congenital valvular aortic stenosis, and hypoplastic left heart syndrome, (19,20) suggesting an oligogenetic pattern of inheritance in those families.…”

Section: Epidemiology and Geneticsmentioning

confidence: 99%