Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Page, Donna J.; Miossec, Matthieu J.; Williams, Simon G.; Monaghan, Richard M.; Fotiou, Elisavet; Cordell, Heather J.; Sutcliffe, Louise; Töpf, Ana; Bourgey, Mathieu; Bourque, Guillaume; Eveleigh, Robert; Dunwoodie, Sally L.; Winlaw, David S.; Bhattacharya, Shoumo; Breckpot, Jeroen; Devriendt, Koenraad; Gewillig, Marc; Brook, J. David; Setchfield, Kerry; Bu’Lock, Frances; O’Sullivan, John; Stuart, Graham; Bezzina, Connie R.; Mulder, Barbara J.M.; Postma, Alex V.; Bentham, James R.; Baron, Martín; Bhaskar, Sanjeev S.; Black, Graeme C M; Newman, William G.; Hentges, Kathryn E.; Lathrop, G.M.; Santibanez‐Koref, Mauro; Keavney, Bernard

doi:10.1161/circresaha.118.313250

Cited by 128 publications

(216 citation statements)

References 78 publications

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“…Although we surveyed nine likely pathogenic variants in the family members but none of them were completely segregated except one, c.T6797C in the NOTCH1 gene, and this illustrates the complexity of the CHD causing identification. According to the previous studies 11,[26][27][28] 31 Gerhardt et al generated knockout mice lacking NOTCH1 TAD to investigate the role of this domain, their functional assays displayed the importance of the TAD in mammalian cardiac development. 32 NOTCH1 variants have been observed in several types of CHD including BAV, 33 AS, HLHS, COA, TOF, 34 left ventricular outflow tract obstructive (LVOTO), 35 and pulmonary stenosis (PS).…”

Section: Discussionmentioning

confidence: 99%

“…7 Mutations in NOTCH1 gene are reported in a range of CHD, comprising bicuspid aortic valve (BAV), 8 aortic stenosis (AS), 9 hypoplastic left heart syndrome (HLHS), 10 coarctation of the aorta (COA), 5 and tetralogy of fallot (TOF). 11 At present, based on Human Gene Mutation Database (HGMD) (www.hgmd.cf.ac.uk), 30 mutations causing CHD have been introduced in the NOTCH1 gene including 21 missenses/nonsenses, three splicings, two small deletions, and 4 gross deletions. To our knowledge, no NOTCH1 mutations were observed in Iranian CHD patients.…”

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confidence: 99%

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A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non‐syndromic congenital heart disease

Kalayinia

Maleki

Mahdavi

et al. 2019

Clinical Laboratory Analysis

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Background Congenital heart disease (CHD) is the most common birth defect which can arises from different genetic defects. The genetic heterogeneity of this disease leads to restricted success in candidate genes screening method. Emerging approaches such as next‐generation sequencing (NGS)‐based genetic analysis might provide a better understating of CHD etiology in the patients who are left undiagnosed. To this aim, in this study, we survived the causes of CHD in an Iranian family who was consanguineous and had two affected children. Methods Affected individuals of this family were checked previously by PCR‐direct sequencing for six candidate genes (NKX2‐5, ZIC3, NODAL, FOXH1, GJA1, GATA4) and had not revealed any reported CHD causative mutations. Whole‐exome sequencing (WES) was performed on this family probond to determine the underlying cause of CHD, and the identified variants were confirmed and segregated by Sanger sequencing. Results We identified one heterozygous missense mutation, c.T6797C (p.Phe2266Ser), in the NOTCH1 gene, which seems to be the most probably disease causing of this family patients. This mutation was found to be novel and not reported on 1000 Genomes Project, dbSNP, and ExAC. Conclusion Worldwide, mutations in NOTCH1 gene are considered as one of the most known causes of CHD. The found NOTCH1 variant in this family affected individuals was the first report from Iran. Yet again, this result indicates the importance of NOTCH1 screening in CHD patients.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non‐syndromic congenital heart disease

Kalayinia

Maleki

Mahdavi

et al. 2019

Clinical Laboratory Analysis

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“…Mutations in NOTCH1 have been identified in autosomal dominantly inherited CHD consisting primarily of bicuspid aortic valve and are associated with abnormalities of the outflow tracts and semilunar valves (Garg et al, ; Kerstjens‐Frederikse et al, ; Preuss et al, ). Mutations in NOTCH1 in patients with isolated tetralogy of Fallot (TOF) were noted to be the most frequent site of genetic variants accounting for 4.5% of patients in one study (Page et al, ).…”

Section: Monogenic Causes Of Isolated Chdmentioning

confidence: 99%

The genetics of isolated congenital heart disease

Nees

Chung

2019

American J of Med Genetics Pt C

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The genetic mechanisms underlying congenital heart disease (CHD) are complex and remain incompletely understood. The majority of patients with CHD have an isolated heart defect without other organ system involvement, but the genetic basis of isolated CHD has been even more difficult to elucidate compared to syndromic CHD. Our understanding of the genetics of isolated CHD is advancing in large part due to advances in next generation sequencing, and the list of genes associated with CHD is rapidly expanding. Variants in hundreds of genes have been identified that may cause or contribute to CHD, but a genetic cause can still only be identified in about 20–30% of patients. Identifying a genetic cause for CHD can have an impact on clinical outcomes and prognosis and thus it is important for clinicians to understand when and what to test in patients with isolated CHD. This chapter reviews some of the known genetic mechanisms that contribute to isolated inherited and sporadic CHD as well as recommendations for evaluation and genetic testing in patients with isolated CHD.

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“…The results suggested the importance of VEGF signaling; however, the statistical burden was not systematically investigated. Another recent multi-centre exome sequencing study of 829 patients with TOF reported genome-wide significant (p-value ≤5×10 −8 ) excess of ultra-rare (absent from a public exome database and other reference data) deleterious variants for FLT4 and NOTCH1 (8). Loss-of-function variants predominated for FLT4 , and missense variants for NOTCH1 (8).…”

Section: Introductionmentioning

confidence: 99%

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Manshaei

Merico

Reuter

et al. 2020

Preprint

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Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD).To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF or related CHD. We adapted a burden test originally developed for de novo variants to assess singleton variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets, and for multiple testing.The gene burden test identified a significant burden of deleterious missense variants in NOTCH1 (Bonferroni-corrected p-value <0.01). These NOTCH1 variants showed significant enrichment for those affecting the extracellular domain, and especially for disruption of cysteine residues forming disulfide bonds (OR 39.8 vs gnomAD). Individuals with NOTCH1 variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in TOF had more modest statistical support and singleton missense variant results were non-significant for gene-set burden. For singleton truncating variants, the gene burden test confirmed significant burden in FLT4. Gene-set burden tests identified a cluster of pathways corresponding to VEGF signaling (FDR=0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR=0.8%), that suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Analyses using unrelated sequencing datasets supported specificity of the findings for CHD.The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.Author summaryWe analyzed the ultra-rare nonsynonymous variant burden for genome sequencing data from 231 individuals with congenital heart defects, most with tetralogy of Fallot. We adapted a burden test originally developed for de novo variants. In line with other studies, we identified a significant truncating variant burden for FLT4 and deleterious missense burden for NOTCH1, both passing a stringent Bonferroni multiple-test correction. For NOTCH1, we observed frequent disruption of cysteine residues establishing disulfide bonds in the extracellular domain. We also identified genes with BH-FDR <10% that were not previously implicated. To overcome limited power for individual genes, we tested gene-sets corresponding to functional pathways and mouse phenotypes. Gene-set burden of truncating variants was significant for vascular endothelial growth factor signaling and abnormal vasculature phenotypes. These results confirmed previous findings and suggested additional candidate genes for experimental validation in future studies. This methodology can be extended to other case-only sequencing data in which ultra-rare variants make a substantial contribution to genetic etiology.

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Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Cited by 128 publications

References 78 publications

A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non‐syndromic congenital heart disease

A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non‐syndromic congenital heart disease

The genetics of isolated congenital heart disease

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

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