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

Donna J. Page, Matthieu J. Miossec, Simon G. Williams, Richard M. Monaghan, Elisavet Fotiou, Heather J. Cordell, Louise Sutcliffe, Ana Topf, Mathieu Bourgey, Guillaume Bourque, Robert Eveleigh, Sally L. Dunwoodie, David S. Winlaw, Shoumo Bhattacharya, Jeroen Breckpot, Koenraad Devriendt, Marc Gewillig, J. David Brook, Kerry J. Setchfield, Frances A. Bu'Lock & 14 otros John O'Sullivan, Graham Stuart, Connie R. Bezzina, Barbara J.M. Mulder, Alex V. Postma, James R. Bentham, Martin Baron, Sanjeev S. Bhaskar, Graeme C. Black, William G. Newman, Kathryn E. Hentges, G. Mark Lathrop, Mauro Santibanez-Koref, Bernard D. Keavney

Resultado de la investigación: Article

3 Citas (Scopus)

Resumen

RATIONALE: 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.

Idioma originalEnglish
Páginas (desde-hasta)553-563
Número de páginas11
PublicaciónCirculation Research
Volumen124
N.º4
DOI
EstadoPublished - 15 feb 2019

Huella dactilar

Exome
Tetralogy of Fallot
Lymphedema
Heart Diseases
Genome
Genes
Cluster Analysis
Parents
Databases
Phenotype
Recurrence

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Citar esto

Page, D. J., Miossec, M. J., Williams, S. G., Monaghan, R. M., Fotiou, E., Cordell, H. J., ... Keavney, B. D. (2019). Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. Circulation Research, 124(4), 553-563. https://doi.org/10.1161/CIRCRESAHA.118.313250
Page, Donna J. ; Miossec, Matthieu J. ; Williams, Simon G. ; Monaghan, Richard M. ; Fotiou, Elisavet ; Cordell, Heather J. ; Sutcliffe, Louise ; Topf, 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 J. ; Bu'Lock, Frances A. ; O'Sullivan, John ; Stuart, Graham ; Bezzina, Connie R. ; Mulder, Barbara J.M. ; Postma, Alex V. ; Bentham, James R. ; Baron, Martin ; Bhaskar, Sanjeev S. ; Black, Graeme C. ; Newman, William G. ; Hentges, Kathryn E. ; Lathrop, G. Mark ; Santibanez-Koref, Mauro ; Keavney, Bernard D. / Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. En: Circulation Research. 2019 ; Vol. 124, N.º 4. pp. 553-563.
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title = "Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot",
abstract = "RATIONALE: 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.",
keywords = "genes, genetic variation, heart diseases, Tetralogy of Fallot, whole exome sequencing",
author = "Page, {Donna J.} and Miossec, {Matthieu J.} and Williams, {Simon G.} and Monaghan, {Richard M.} and Elisavet Fotiou and Cordell, {Heather J.} and Louise Sutcliffe and Ana Topf and Mathieu Bourgey and Guillaume Bourque and Robert Eveleigh and Dunwoodie, {Sally L.} and Winlaw, {David S.} and Shoumo Bhattacharya and Jeroen Breckpot and Koenraad Devriendt and Marc Gewillig and Brook, {J. David} and Setchfield, {Kerry J.} and Bu'Lock, {Frances A.} and John O'Sullivan and Graham Stuart and Bezzina, {Connie R.} and Mulder, {Barbara J.M.} and Postma, {Alex V.} and Bentham, {James R.} and Martin Baron and Bhaskar, {Sanjeev S.} and Black, {Graeme C.} and Newman, {William G.} and Hentges, {Kathryn E.} and Lathrop, {G. Mark} and Mauro Santibanez-Koref and Keavney, {Bernard D.}",
year = "2019",
month = "2",
day = "15",
doi = "10.1161/CIRCRESAHA.118.313250",
language = "English",
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journal = "Circulation Research",
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publisher = "Lippincott Williams and Wilkins",
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Page, DJ, Miossec, MJ, Williams, SG, Monaghan, RM, Fotiou, E, Cordell, HJ, Sutcliffe, L, Topf, A, Bourgey, M, Bourque, G, Eveleigh, R, Dunwoodie, SL, Winlaw, DS, Bhattacharya, S, Breckpot, J, Devriendt, K, Gewillig, M, Brook, JD, Setchfield, KJ, Bu'Lock, FA, O'Sullivan, J, Stuart, G, Bezzina, CR, Mulder, BJM, Postma, AV, Bentham, JR, Baron, M, Bhaskar, SS, Black, GC, Newman, WG, Hentges, KE, Lathrop, GM, Santibanez-Koref, M & Keavney, BD 2019, 'Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot', Circulation Research, vol. 124, n.º 4, pp. 553-563. https://doi.org/10.1161/CIRCRESAHA.118.313250

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; Topf, 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 J.; Bu'Lock, Frances A.; O'Sullivan, John; Stuart, Graham; Bezzina, Connie R.; Mulder, Barbara J.M.; Postma, Alex V.; Bentham, James R.; Baron, Martin; Bhaskar, Sanjeev S.; Black, Graeme C.; Newman, William G.; Hentges, Kathryn E.; Lathrop, G. Mark; Santibanez-Koref, Mauro; Keavney, Bernard D.

En: Circulation Research, Vol. 124, N.º 4, 15.02.2019, p. 553-563.

Resultado de la investigación: Article

TY - JOUR

T1 - Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

AU - Page, Donna J.

AU - Miossec, Matthieu J.

AU - Williams, Simon G.

AU - Monaghan, Richard M.

AU - Fotiou, Elisavet

AU - Cordell, Heather J.

AU - Sutcliffe, Louise

AU - Topf, Ana

AU - Bourgey, Mathieu

AU - Bourque, Guillaume

AU - Eveleigh, Robert

AU - Dunwoodie, Sally L.

AU - Winlaw, David S.

AU - Bhattacharya, Shoumo

AU - Breckpot, Jeroen

AU - Devriendt, Koenraad

AU - Gewillig, Marc

AU - Brook, J. David

AU - Setchfield, Kerry J.

AU - Bu'Lock, Frances A.

AU - O'Sullivan, John

AU - Stuart, Graham

AU - Bezzina, Connie R.

AU - Mulder, Barbara J.M.

AU - Postma, Alex V.

AU - Bentham, James R.

AU - Baron, Martin

AU - Bhaskar, Sanjeev S.

AU - Black, Graeme C.

AU - Newman, William G.

AU - Hentges, Kathryn E.

AU - Lathrop, G. Mark

AU - Santibanez-Koref, Mauro

AU - Keavney, Bernard D.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - RATIONALE: 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.

AB - RATIONALE: 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.

KW - genes

KW - genetic variation

KW - heart diseases

KW - Tetralogy of Fallot

KW - whole exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85061591946&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.118.313250

DO - 10.1161/CIRCRESAHA.118.313250

M3 - Article

VL - 124

SP - 553

EP - 563

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 4

ER -