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The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease.
Reuter, Miriam S; Chaturvedi, Rajiv R; Liston, Eriskay; Manshaei, Roozbeh; Aul, Ritu B; Bowdin, Sarah; Cohn, Iris; Curtis, Meredith; Dhir, Priya; Hayeems, Robin Z; Hosseini, S Mohsen; Khan, Reem; Ly, Linh G; Marshall, Christian R; Mertens, Luc; Okello, John B A; Pereira, Sergio L; Raajkumar, Akshaya; Seed, Mike; Thiruvahindrapuram, Bhooma; Scherer, Stephen W; Kim, Raymond H; Jobling, Rebekah K.
Afiliação
  • Reuter MS; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Chaturvedi RR; CGEn, The Hospital for Sick Children, Toronto, ON, Canada.
  • Liston E; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
  • Manshaei R; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Aul RB; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Bowdin S; Labatt Heart Centre, Division of Cardiology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Cohn I; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Curtis M; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
  • Dhir P; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Hayeems RZ; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Hosseini SM; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
  • Khan R; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Ly LG; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
  • Marshall CR; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Mertens L; Divisions of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
  • Okello JBA; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Pereira SL; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Raajkumar A; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
  • Seed M; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Thiruvahindrapuram B; Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada.
  • Scherer SW; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Kim RH; Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
  • Jobling RK; Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada.
Genet Med ; 22(6): 1015-1024, 2020 06.
Article em En | MEDLINE | ID: mdl-32037394
ABSTRACT

PURPOSE:

This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.

METHODS:

We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation.

RESULTS:

In 14 families (12.6%), we identified causative variants seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis.

CONCLUSION:

This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cardiopatias Tipo de estudo: Prognostic_studies Limite: Child / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Cardiopatias Tipo de estudo: Prognostic_studies Limite: Child / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article