K Nicole Weaver1,2,3, Jing Chen4,3, Amy Shikany2, Pete S White3, Carlos E Prada5,6, Bruce D Gelb7, James F Cnota2,3. 1. Division of Human Genetics (K.N.W.), Cincinnati Children's Hospital Medical Center. 2. Heart Institute (K.N.W., A.S., J.F.C.), Cincinnati Children's Hospital Medical Center. 3. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (K.N.W., J.C., P.S.W., J.F.C.). 4. Division of Biomedical Informatics (J.C.), Cincinnati Children's Hospital Medical Center. 5. Division of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago (C.E.P.). 6. Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL (C.E.P.). 7. Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY (B.D.G.).
Abstract
BACKGROUND: Valvar pulmonary stenosis (vPS) accounts for 8% to 12% of congenital heart disease cases. Multiple genetic syndromes are associated with vPS, most commonly Noonan syndrome, but the cause is unknown in most cases. We analyzed genomic data from a large cohort with vPS to determine the prevalence of genetic diagnosis. METHODS: The Pediatric Cardiac Genomics Consortium database was queried to identify probands with vPS without complex congenital heart disease or aneuploidy and with existing whole exome or genome sequencing. A custom analysis workflow was used to identify likely pathogenic or pathogenic variants in disease-associated genes. Demographic and phenotypic characteristics were compared between groups with and without molecular diagnoses. RESULTS: Data from 119 probands (105 trios) were included. A molecular diagnosis was identified in 22 (18%); 17 (14%) had Noonan syndrome or a related disorder. Extracardiac and neurodevelopmental comorbidities were seen in 67/119 (56%) of probands. Molecular diagnosis was more common in those with extracardiac and neurodevelopmental phenotypes than those without (18/67 versus 4/52, P=0.0086). CONCLUSIONS: Clinicians should have high suspicion for a genetic diagnosis in individuals with vPS, particularly if additional phenotypes are present. Our results suggest that clinicians should consider offering sequencing of at least the known congenital heart disease and RASopathy genes to all individuals with vPS, regardless of whether that individual has extracardiac or neurodevelopmental phenotypes present.
BACKGROUND: Valvar pulmonary stenosis (vPS) accounts for 8% to 12% of congenital heart disease cases. Multiple genetic syndromes are associated with vPS, most commonly Noonan syndrome, but the cause is unknown in most cases. We analyzed genomic data from a large cohort with vPS to determine the prevalence of genetic diagnosis. METHODS: The Pediatric Cardiac Genomics Consortium database was queried to identify probands with vPS without complex congenital heart disease or aneuploidy and with existing whole exome or genome sequencing. A custom analysis workflow was used to identify likely pathogenic or pathogenic variants in disease-associated genes. Demographic and phenotypic characteristics were compared between groups with and without molecular diagnoses. RESULTS: Data from 119 probands (105 trios) were included. A molecular diagnosis was identified in 22 (18%); 17 (14%) had Noonan syndrome or a related disorder. Extracardiac and neurodevelopmental comorbidities were seen in 67/119 (56%) of probands. Molecular diagnosis was more common in those with extracardiac and neurodevelopmental phenotypes than those without (18/67 versus 4/52, P=0.0086). CONCLUSIONS: Clinicians should have high suspicion for a genetic diagnosis in individuals with vPS, particularly if additional phenotypes are present. Our results suggest that clinicians should consider offering sequencing of at least the known congenital heart disease and RASopathy genes to all individuals with vPS, regardless of whether that individual has extracardiac or neurodevelopmental phenotypes present.
Authors: Sue Richards; Nazneen Aziz; Sherri Bale; David Bick; Soma Das; Julie Gastier-Foster; Wayne W Grody; Madhuri Hegde; Elaine Lyon; Elaine Spector; Karl Voelkerding; Heidi L Rehm Journal: Genet Med Date: 2015-03-05 Impact factor: 8.822
Authors: Monkol Lek; Konrad J Karczewski; Eric V Minikel; Kaitlin E Samocha; Eric Banks; Timothy Fennell; Anne H O'Donnell-Luria; James S Ware; Andrew J Hill; Beryl B Cummings; Taru Tukiainen; Daniel P Birnbaum; Jack A Kosmicki; Laramie E Duncan; Karol Estrada; Fengmei Zhao; James Zou; Emma Pierce-Hoffman; Joanne Berghout; David N Cooper; Nicole Deflaux; Mark DePristo; Ron Do; Jason Flannick; Menachem Fromer; Laura Gauthier; Jackie Goldstein; Namrata Gupta; Daniel Howrigan; Adam Kiezun; Mitja I Kurki; Ami Levy Moonshine; Pradeep Natarajan; Lorena Orozco; Gina M Peloso; Ryan Poplin; Manuel A Rivas; Valentin Ruano-Rubio; Samuel A Rose; Douglas M Ruderfer; Khalid Shakir; Peter D Stenson; Christine Stevens; Brett P Thomas; Grace Tiao; Maria T Tusie-Luna; Ben Weisburd; Hong-Hee Won; Dongmei Yu; David M Altshuler; Diego Ardissino; Michael Boehnke; John Danesh; Stacey Donnelly; Roberto Elosua; Jose C Florez; Stacey B Gabriel; Gad Getz; Stephen J Glatt; Christina M Hultman; Sekar Kathiresan; Markku Laakso; Steven McCarroll; Mark I McCarthy; Dermot McGovern; Ruth McPherson; Benjamin M Neale; Aarno Palotie; Shaun M Purcell; Danish Saleheen; Jeremiah M Scharf; Pamela Sklar; Patrick F Sullivan; Jaakko Tuomilehto; Ming T Tsuang; Hugh C Watkins; James G Wilson; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2016-08-18 Impact factor: 49.962
Authors: Lauge Farnaes; Amber Hildreth; Nathaly M Sweeney; Michelle M Clark; Shimul Chowdhury; Shareef Nahas; Julie A Cakici; Wendy Benson; Robert H Kaplan; Richard Kronick; Matthew N Bainbridge; Jennifer Friedman; Jeffrey J Gold; Yan Ding; Narayanan Veeraraghavan; David Dimmock; Stephen F Kingsmore Journal: NPJ Genom Med Date: 2018-04-04 Impact factor: 8.617
Authors: Samir Zaidi; Murim Choi; Hiroko Wakimoto; Lijiang Ma; Jianming Jiang; John D Overton; Angela Romano-Adesman; Robert D Bjornson; Roger E Breitbart; Kerry K Brown; Nicholas J Carriero; Yee Him Cheung; John Deanfield; Steve DePalma; Khalid A Fakhro; Joseph Glessner; Hakon Hakonarson; Michael J Italia; Jonathan R Kaltman; Juan Kaski; Richard Kim; Jennie K Kline; Teresa Lee; Jeremy Leipzig; Alexander Lopez; Shrikant M Mane; Laura E Mitchell; Jane W Newburger; Michael Parfenov; Itsik Pe'er; George Porter; Amy E Roberts; Ravi Sachidanandam; Stephan J Sanders; Howard S Seiden; Mathew W State; Sailakshmi Subramanian; Irina R Tikhonova; Wei Wang; Dorothy Warburton; Peter S White; Ismee A Williams; Hongyu Zhao; Jonathan G Seidman; Martina Brueckner; Wendy K Chung; Bruce D Gelb; Elizabeth Goldmuntz; Christine E Seidman; Richard P Lifton Journal: Nature Date: 2013-05-12 Impact factor: 49.962