Justin O Szot1, Hartmut Cuny1, Gillian M Blue1, David T Humphreys1, Eddie Ip1, Katrina Harrison1, Gary F Sholler1, Eleni Giannoulatou1, Paul Leo1, Emma L Duncan1, Duncan B Sparrow1, Joshua W K Ho1, Robert M Graham1, Nicholas Pachter1, Gavin Chapman1, David S Winlaw1, Sally L Dunwoodie2. 1. From the Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (J.O.S., H.C., D.T.H., E.I., E.G., D.B.S., J.W.K.H., R.M.G., G.C., S.L.D.); Faculty of Science (J.O.S., S.L.D.) and Faculty of Medicine (H.C., D.T.H., E.I., E.G., D.B.S., J.W.K.H., R.M.G., G.C., S.L.D.), University of New South Wales, Sydney, New South Wales, Australia, Sydney, New South Wales, Australia; Children's Hospital at Westmead, Heart Centre for Children (G.M.B., G.F.S., D.S.W.), Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, New South Wales, Australia (G.M.B., G.F.S., D.S.W.); Genetic Services of Western Australia, Perth (K.H., N.P.); Sydney Children's Hospitals Network, New South Wales, Australia (G.F.S.); Institute of Health and Biomedical Innovation, Queensland University of Technology (P.L., E.L.D.); Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia (E.L.D.); University of Queensland, Brisbane (E.L.D.); and School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia (N.P.). 2. From the Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (J.O.S., H.C., D.T.H., E.I., E.G., D.B.S., J.W.K.H., R.M.G., G.C., S.L.D.); Faculty of Science (J.O.S., S.L.D.) and Faculty of Medicine (H.C., D.T.H., E.I., E.G., D.B.S., J.W.K.H., R.M.G., G.C., S.L.D.), University of New South Wales, Sydney, New South Wales, Australia, Sydney, New South Wales, Australia; Children's Hospital at Westmead, Heart Centre for Children (G.M.B., G.F.S., D.S.W.), Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, New South Wales, Australia (G.M.B., G.F.S., D.S.W.); Genetic Services of Western Australia, Perth (K.H., N.P.); Sydney Children's Hospitals Network, New South Wales, Australia (G.F.S.); Institute of Health and Biomedical Innovation, Queensland University of Technology (P.L., E.L.D.); Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia (E.L.D.); University of Queensland, Brisbane (E.L.D.); and School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia (N.P.). s.dunwoodie@victorchang.edu.au.
Abstract
BACKGROUND: Congenital heart disease (CHD)-structural abnormalities of the heart that arise during embryonic development-is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD. METHODS: Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. RESULTS: In 3 families (10%), we found pathogenic variants in known CHD genes TBX5, TFAP2B, and PTPN11, explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in PBX1, CNOT1, ZFP36L2, TEK, USP34, UPF2, KDM5A, KMT2C, TIE1, TEAD2, and FLT4. CONCLUSIONS: The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.
BACKGROUND:Congenital heart disease (CHD)-structural abnormalities of the heart that arise during embryonic development-is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD. METHODS: Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. RESULTS: In 3 families (10%), we found pathogenic variants in known CHD genes TBX5, TFAP2B, and PTPN11, explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in PBX1, CNOT1, ZFP36L2, TEK, USP34, UPF2, KDM5A, KMT2C, TIE1, TEAD2, and FLT4. CONCLUSIONS: The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.
Authors: Gavin Chapman; Julie L M Moreau; Eddie I P; Justin O Szot; Kavitha R Iyer; Hongjun Shi; Michelle X Yam; Victoria C O'Reilly; Annabelle Enriquez; Joelene A Greasby; Dimuthu Alankarage; Ella M M A Martin; Bernadette C Hanna; Matthew Edwards; Steven Monger; Gillian M Blue; David S Winlaw; Helen E Ritchie; Stuart M Grieve; Eleni Giannoulatou; Duncan B Sparrow; Sally L Dunwoodie Journal: Hum Mol Genet Date: 2020-03-13 Impact factor: 6.150
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Dimuthu Alankarage; Justin O Szot; Nick Pachter; Anne Slavotinek; Licia Selleri; Joseph T Shieh; David Winlaw; Eleni Giannoulatou; Gavin Chapman; Sally L Dunwoodie Journal: Hum Mol Genet Date: 2020-05-08 Impact factor: 6.150
Authors: 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; 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 Journal: Circ Res Date: 2019-02-15 Impact factor: 17.367
Authors: Ilse Meerschaut; Sarah Vergult; Annelies Dheedene; Björn Menten; Katya De Groote; Hans De Wilde; Laura Muiño Mosquera; Joseph Panzer; Kristof Vandekerckhove; Paul J Coucke; Daniël De Wolf; Bert Callewaert Journal: Genes (Basel) Date: 2021-07-08 Impact factor: 4.096