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3 results on '"Mital, S. (Seema)"'

1. A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy

Author

Miron, A. (Anastasia), Lafreniere-Roula, M. (Myriam), Steve Fan, C.-P. (Chun-Po), Armstrong, K.R. (Katey R.), Dragulescu, A. (Andreea), Papaz, T. (Tanya), Manlhiot, C. (Cedric), Kaufman, B. (Beth), Butts, R.J. (Ryan J.), Gardin, L. (Letizia), Stephenson, E.A. (Elizabeth A.), Howard, T.S. (Taylor S.), Aziz, P.F. (Pete F.), Balaji, S. (Seshadri), Ladouceur, V.B. (Virginie Beauséjour), Benson, L.N. (Lee N.), Colan, S.D. (Steven), Godown, J. (Justin), Henderson, H.T. (Heather T.), Ingles, J. (Jodie), Jeewa, A. (Aamir), Jefferies, J.L. (John L.), Lal, A.K. (Ashwin K.), Mathew, J. (Jacob), Jean-St-Michel, E. (Emilie), Michels, M. (Michelle), Nakano, S.J. (Stephanie J.), Olivotto, I. (Iacopo), Parent, J.J. (John J.), Pereira, A. (A.), Semsarian, C. (Christopher), Whitehill, R.D. (Robert D.), Wittekind, S.G. (Samuel G.), Russell, M.W. (Mark W.), Conway, J. (Jennifer), Richmond, M.E. (Marc E.), Villa, C. (Chet), Weintraub, R.G. (Robert G), Rossano, J.W. (Joseph W.), Kantor, P.F. (Paul F.), Ho, C.Y. (Carolyn Y.), Mital, S. (Seema), Miron, A. (Anastasia), Lafreniere-Roula, M. (Myriam), Steve Fan, C.-P. (Chun-Po), Armstrong, K.R. (Katey R.), Dragulescu, A. (Andreea), Papaz, T. (Tanya), Manlhiot, C. (Cedric), Kaufman, B. (Beth), Butts, R.J. (Ryan J.), Gardin, L. (Letizia), Stephenson, E.A. (Elizabeth A.), Howard, T.S. (Taylor S.), Aziz, P.F. (Pete F.), Balaji, S. (Seshadri), Ladouceur, V.B. (Virginie Beauséjour), Benson, L.N. (Lee N.), Colan, S.D. (Steven), Godown, J. (Justin), Henderson, H.T. (Heather T.), Ingles, J. (Jodie), Jeewa, A. (Aamir), Jefferies, J.L. (John L.), Lal, A.K. (Ashwin K.), Mathew, J. (Jacob), Jean-St-Michel, E. (Emilie), Michels, M. (Michelle), Nakano, S.J. (Stephanie J.), Olivotto, I. (Iacopo), Parent, J.J. (John J.), Pereira, A. (A.), Semsarian, C. (Christopher), Whitehill, R.D. (Robert D.), Wittekind, S.G. (Samuel G.), Russell, M.W. (Mark W.), Conway, J. (Jennifer), Richmond, M.E. (Marc E.), Villa, C. (Chet), Weintraub, R.G. (Robert G), Rossano, J.W. (Joseph W.), Kantor, P.F. (Paul F.), Ho, C.Y. (Carolyn Y.), and Mital, S. (Seema)

Abstract

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). Results: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic mode

Published
2020
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2. Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor

Author

Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Beek, G. (Gerarda van de), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Laer, L. (Lut) van, Verhagen, J.M.A. (Judith), Laar, I.M.B.H. (Ingrid) van de, Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), Loeys, B.L. (Bart), Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Beek, G. (Gerarda van de), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Laer, L. (Lut) van, Verhagen, J.M.A. (Judith), Laar, I.M.B.H. (Ingrid) van de, Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), and Loeys, B.L. (Bart)

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter = 4.0 cm in adults, or a Z-score = 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.

Published
2017
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3. Corrigendum: Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor [Front. Physiol, 8, (2017) (400)] doi: 10.3389/fphys.2017.00400

Author

Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Van De Beek, G. (Gerarda), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Van Laer, L. (Lut), Verhagen, J.M.A. (Judith), van de Laar, I.M.B.H. (Ingrid M.B.H.), Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), Loeys, B.L. (Bart), Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Van De Beek, G. (Gerarda), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Van Laer, L. (Lut), Verhagen, J.M.A. (Judith), van de Laar, I.M.B.H. (Ingrid M.B.H.), Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), and Loeys, B.L. (Bart)

Abstract

In the original article, we noted two mutation annotation errors. The correction of these two mistakes does not change the scientific conclusions in any way. The authors apologize for these nomenclature errors. Please find below the corrected annotations of those two mutations: (1) The correct RNA and protein annotations of the SMAD6 variant in P99 are c.455_461del and p.Pro152Profs*27, and not c.454_461del and p.Gly166Valfs*23. (2) The correct RNA and protein annotations of the SMAD6 variant in P128 are c.74_79del and p.Ser27_Gly28del, and not c.73_79del and p.Gly26_Ser27del. As a consequence, a correction has been made to RESULTS, Paragraphs 5 and 6: The SMAD6 c.726del variant leads to a frameshift (p.Lys242Asnfs*300) and a predicted protein with a C-terminal extension due to loss of the intended stop codon. The c.455_461del frameshift variant (p.Pro152Profs*27) causes the introduction of a premature stop codon, most likely resulting in haploinsufficiency due to nonsense-mediated mRNA decay (NMD). Also the two nonsense variants (p.Tyr279* and p.Tyr288*) are predicted to lead to NMD. All of the missense variants cluster in the functionally important MH1 and MH2 domains (Makkar et al., 2009) (amino acids 148-275 and 331-496, respectively), which is not the case for the sole missense variant (p.Ser130Leu) found in a control individual (Figure 2). All but one (p.Arg443His) of the identified variants were absent in the ExAC control cohort (v0.3.1; Supplementary Table 2). Moreover, the missense variants in the patient cohort (7/7) are enriched in the MH1 and MH2 domains when compared to ExAC controls (n = 228/430; p = 0.02).

Published
2017
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