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Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes.
Blue, Gillian M; Mekel, Mauk; Das, Debjani; Troup, Michael; Rath, Emma; Ip, Eddie; Gudkov, Mikhail; Perumal, Gopinath; Harvey, Richard P; Sholler, Gary F; Gecz, Jozef; Kirk, Edwin P; Liu, Jinfen; Giannoulatou, Eleni; Hong, Haifa; Dunwoodie, Sally L; Winlaw, David S.
Afiliação
  • Blue GM; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
  • Mekel M; Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Das D; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
  • Troup M; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
  • Rath E; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia.
  • Ip E; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
  • Gudkov M; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
  • Perumal G; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia.
  • Harvey RP; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia; School of Biotechnology and Biomolecular Science, UNSW Sydney, Sydney, Australia.
  • Sholler GF; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia.
  • Gecz J; Adelaide Medical School, The University of Adelaide, Adelaide, Australia.
  • Kirk EP; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia; School of Women's and Children's Health, Faculty of Medicine, UNSW Sydney, Sydney, Australia.
  • Liu J; The Cardiothoracic Surgery Department, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • Giannoulatou E; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia.
  • Hong H; The Cardiothoracic Surgery Department, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • Dunwoodie SL; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia.
  • Winlaw DS; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, The University of Sydney, Sydney, Australia; Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Aus
Am Heart J ; 244: 1-13, 2022 02.
Article em En | MEDLINE | ID: mdl-34670123
ABSTRACT

BACKGROUND:

The most common cyanotic congenital heart disease (CHD) requiring management as a neonate is transposition of great arteries (TGA). Clinically, up to 50% of TGA patients develop some form of neurodevelopmental disability (NDD), thought to have a significant genetic component. A "ciliopathy" and links with laterality disorders have been proposed. This first report of whole genome sequencing in TGA, sought to identify clinically relevant variants contributing to heart, brain and laterality defects.

METHODS:

Initial whole genome sequencing analyses on 100 TGA patients focussed on established disease genes related to CHD (n = 107), NDD (n = 659) and heterotaxy (n = 74). Single variant as well as copy number variant analyses were conducted. Variant pathogenicity was assessed using the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.

RESULTS:

Fifty-five putatively damaging variants were identified in established disease genes associated with CHD, NDD and heterotaxy; however, no clinically relevant variants could be attributed to disease. Notably, case-control analyses identified significantly more predicted-damaging, silent and total variants in TGA cases than healthy controls in established CHD genes (P < .001), NDD genes (P < .001) as well as across the three gene panels (P < .001).

CONCLUSION:

We present compelling evidence that the majority of TGA is not caused by monogenic rare variants and is most likely oligogenic and/or polygenic in nature, highlighting the complex genetic architecture and multifactorial influences on this CHD sub-type and its long-term sequelae. Assessment of variant burden in key heart, brain and/or laterality genes may be required to unravel the genetic contributions to TGA and related disabilities.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transposição dos Grandes Vasos / Cardiopatias Congênitas Tipo de estudo: Guideline / Risk_factors_studies Limite: Humans / Newborn Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transposição dos Grandes Vasos / Cardiopatias Congênitas Tipo de estudo: Guideline / Risk_factors_studies Limite: Humans / Newborn Idioma: En Ano de publicação: 2022 Tipo de documento: Article