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

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dc.contributor.authorPage, Donna J.
dc.contributor.authorMiossec, Matthieu J.
dc.contributor.authorWilliams, Simon G.
dc.contributor.authorMonaghan, Richard M.
dc.contributor.authorFotiou, Elisavet
dc.contributor.authorCordell, Heather J.
dc.contributor.authorSutcliffe, Louise
dc.contributor.authorTopf, Ana
dc.contributor.authorBourgey, Mathieu
dc.contributor.authorBourque, Guillaume
dc.contributor.authorEveleigh, Robert
dc.contributor.authorDunwoodie, Sally L.
dc.contributor.authorWinlaw, David S.
dc.contributor.authorBhattacharya, Shoumo
dc.contributor.authorBreckpot, Jeroen
dc.contributor.authorDevriendt, Koenraad
dc.contributor.authorGewillig, Marc
dc.contributor.authorBrook, J. David
dc.contributor.authorSetchfield, Kerry J.
dc.contributor.authorBu'Lock, Frances A.
dc.contributor.authorO'Sullivan, John
dc.contributor.authorStuart, Graham
dc.contributor.authorBezzina, Connie R.
dc.contributor.authorMulder, Barbara J. M.
dc.contributor.authorPostma, Alex V.
dc.contributor.authorBentham, James R.
dc.contributor.authorBaron, Martin
dc.contributor.authorBhaskar, Sanjeev S.
dc.contributor.authorBlack, Graeme C.
dc.contributor.authorNewman, William G.
dc.contributor.authorHentges, Kathryn E.
dc.contributor.authorLathrop, G. Mark
dc.contributor.authorSantibanez-Koref, Mauro
dc.contributor.authorKeavney, Bernard D.
dc.date.accessioned2024-06-11T15:45:03Z
dc.date.available2024-06-11T15:45:03Z
dc.date.issued2019
dc.descriptionIndexación: Scopus.
dc.description.abstractRationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. Methods and Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. Conclusions: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.
dc.description.urihttps://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313250
dc.description.urihttps://link.springer.com/article/10.1007/s11069-021-04862-y
dc.identifier.citationCirculation Research 124, Issue 4, Pages 553 - 563 2019
dc.identifier.doi10.1161/CIRCRESAHA.118.313250
dc.identifier.doi10.1007/s11069-021-04862-y
dc.identifier.issn0009-7330
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/57530
dc.language.isoen_US
dc.publisherLippincott Williams and Wilkins
dc.subjectgenes
dc.subjectgenetic variation
dc.subjectheart diseases
dc.subjectTetralogy of Fallot
dc.subjectwhole exome sequencing
dc.titleWhole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot
dc.typeArtículo
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