Cardiomyopathies in 100,000 genomes project: interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery.
100,000 Genomes Project
Cardiomyopathy
Genetic diagnosis
Genome sequencing
Paediatric
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
30
07
2023
accepted:
24
09
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
Cardiomyopathies are clinically important conditions, with a strong genetic component. National genomic initiatives such as 100,000 Genome Project (100KGP) provide opportunity to study these rare conditions at scale beyond conventional research studies. We present the clinical and molecular characteristics of the 100KGP cohort, comparing paediatric and adult probands with diverse cardiomyopathies. We assessed the diagnostic yield and spectrum of genetic aetiologies across clinical presentations. We re-analysed existing genomic data using an updated analytical strategy (revised gene panels; unbiased analyses of de novo variants; and improved variant prioritisation strategies) to identify new causative variants in genetically unsolved children. We identified 1918 individuals (1563 probands, 355 relatives) with cardiomyopathy (CM) in 100KGP. Probands, comprising 273 children and 1290 adults, were enrolled under > 55 different recruitment categories. Paediatric probands had higher rates of co-existing congenital heart disease (12%) compared to adults (0.9%). Diagnostic yield following 100KGP's initial analysis was significantly higher for children (19%) than for adults (11%) with 11% of diagnoses overall made in genes not on the existing UK paediatric or syndromic CM panel. Our re-analysis of paediatric probands yields a potential diagnosis in 40%, identifying new probable or possible diagnoses in 49 previously unsolved paediatric cases. Structural and intronic variants accounted for 11% of all potential diagnoses in children while de novo variants were identified in 17%. 100KGP demonstrates the benefit of genome sequencing over a standalone panel in CM. Re-analysis of paediatric CM probands allowed a significant uplift in diagnostic yield, emphasising the importance of iterative re-evaluation in genomic studies. Despite these efforts, many children with CM remain without a genetic diagnosis, highlighting the need for better gene-disease relationship curation and ongoing data sharing. The 100KGP CM cohort is likely to be useful for further gene discovery, but heterogeneous ascertainment and key technical limitations must be understood and addressed.
Sections du résumé
BACKGROUND
BACKGROUND
Cardiomyopathies are clinically important conditions, with a strong genetic component. National genomic initiatives such as 100,000 Genome Project (100KGP) provide opportunity to study these rare conditions at scale beyond conventional research studies.
METHODS
METHODS
We present the clinical and molecular characteristics of the 100KGP cohort, comparing paediatric and adult probands with diverse cardiomyopathies. We assessed the diagnostic yield and spectrum of genetic aetiologies across clinical presentations. We re-analysed existing genomic data using an updated analytical strategy (revised gene panels; unbiased analyses of de novo variants; and improved variant prioritisation strategies) to identify new causative variants in genetically unsolved children.
RESULTS
RESULTS
We identified 1918 individuals (1563 probands, 355 relatives) with cardiomyopathy (CM) in 100KGP. Probands, comprising 273 children and 1290 adults, were enrolled under > 55 different recruitment categories. Paediatric probands had higher rates of co-existing congenital heart disease (12%) compared to adults (0.9%). Diagnostic yield following 100KGP's initial analysis was significantly higher for children (19%) than for adults (11%) with 11% of diagnoses overall made in genes not on the existing UK paediatric or syndromic CM panel. Our re-analysis of paediatric probands yields a potential diagnosis in 40%, identifying new probable or possible diagnoses in 49 previously unsolved paediatric cases. Structural and intronic variants accounted for 11% of all potential diagnoses in children while de novo variants were identified in 17%.
CONCLUSIONS
CONCLUSIONS
100KGP demonstrates the benefit of genome sequencing over a standalone panel in CM. Re-analysis of paediatric CM probands allowed a significant uplift in diagnostic yield, emphasising the importance of iterative re-evaluation in genomic studies. Despite these efforts, many children with CM remain without a genetic diagnosis, highlighting the need for better gene-disease relationship curation and ongoing data sharing. The 100KGP CM cohort is likely to be useful for further gene discovery, but heterogeneous ascertainment and key technical limitations must be understood and addressed.
Identifiants
pubmed: 39472908
doi: 10.1186/s13073-024-01390-9
pii: 10.1186/s13073-024-01390-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
125Informations de copyright
© 2024. The Author(s).
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