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Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance.
Murphy, Jane; Kirk, Claire W; Lambert, Deborah M; McGorrian, Catherine; Walsh, Roddy; McVeigh, Terri P; Prendiville, Terence; Ward, Deirdre; Galvin, Joseph; Lynch, Sally Ann.
Afiliação
  • Murphy J; School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland. janemurphy19@gmail.com.
  • Kirk CW; School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
  • Lambert DM; School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
  • McGorrian C; Family Heart Screening Clinic, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.
  • Walsh R; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands.
  • McVeigh TP; Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, United Kingdom.
  • Prendiville T; Department of Cardiology, Children's Health Ireland at Crumlin, Crumlin, Dublin 12, Ireland.
  • Ward D; Centre for Cardiac Risk in the Young Persons, Tallaght University Hospital, Dublin 24, Ireland.
  • Galvin J; Family Heart Screening Clinic, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.
  • Lynch SA; Department of Clinical Genetics, Children's Health Ireland at Crumlin, Crumlin, Dublin 12, Ireland.
Ir J Med Sci ; 193(4): 1775-1785, 2024 Aug.
Article em En | MEDLINE | ID: mdl-38489124
ABSTRACT

BACKGROUND:

Inherited cardiomyopathies (HCM, DCM, ACM) and cardiac ion channelopathies (long QT/Brugada syndromes, CPVT) are associated with significant morbidity and mortality; however, diagnosis of a familial pathogenic variant in a proband allows for subsequent cascade screening of their at-risk relatives.

AIMS:

We investigated the diagnostic yield from cardiac gene panel testing and reviewed variants of uncertain significance from patients attending three specialist cardiogenetics services in Ireland in the years 2002 to 2020.

RESULTS:

Reviewing molecular genetic diagnostic reports of 834 patients from 820 families, the initial diagnostic yield of pathogenic/likely pathogenic variants was 237/834 patients (28.4%), increasing to 276/834 patients (33.1%) following re-evaluation of cases with variant(s) of uncertain significance. Altogether, 42/85 patients with VUS reviewed (49.4%) had a re-classification that could change their clinical management. Females were more likely to carry pathogenic/likely pathogenic variants than males (139/374, 37.2% vs 137/460, 29.8%, respectively, p = 0.03), and the diagnostic yields were highest in the 0 to < 2 years age group (6/12, 50.0%) and amongst those tested for cardiomyopathy gene panels (13/35, 37.1%). Variants in the MYBPC3/MYH7 (87/109, 79.8%) and KCNQ1/KCNH2 (91/100, 91.0%) genes were the predominant genetic causes for hypertrophic cardiomyopathy and long QT syndrome, respectively.

CONCLUSION:

Our study highlights the importance of collation and review of pre-ACMG genetic variants to increase diagnostic utility of genetic testing for inherited heart disease. Almost half of patients with pre-ACMG VUS reviewed had their variant re-classified to likely pathogenic/likely benign which resulted in a positive clinical impact for patients and their families.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Testes Genéticos Limite: Adolescent / Adult / Aged / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged País/Região como assunto: Europa Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Testes Genéticos Limite: Adolescent / Adult / Aged / Child / Child, preschool / Female / Humans / Infant / Male / Middle aged País/Região como assunto: Europa Idioma: En Ano de publicação: 2024 Tipo de documento: Article