Study of pathogenic genes in a pedigree with familial dilated cardiomyopathy

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Dilated cardiomyopathy (n=83). Intervention: Whole exome sequencing. Primary outcome: Proportion of patients with a pathogenic or likely pathogenic variant.

Q: What does this research mean for the field?

Whole exome sequencing using stringent ACMG classification criteria identifies pathogenic or likely pathogenic variants in 12% of patients with dilated cardiomyopathy, yielding a lower diagnostic detection rate than previously reported. Novelty: ClaimNovelty.CONTRADICTORY. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

Xinru Zhang; Hang Ren; Fang Yao; Yang Liu; Chunli Song

doi:10.12998/wjcc.v11.i11.2412

April 6, 2023World Journal of Clinical CasesOpen Access

Study of pathogenic genes in a pedigree with familial dilated cardiomyopathy

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Key result

Whole exome sequencing identifies pathogenic variants in ~12% of patients with dilated cardiomyopathy.

n=83

Why the study?

The utility of whole exome sequencing as a first-line genetic test for patients with dilated cardiomyopathy in a real-world clinical setting has not been specifically established.

Key Points

Determine the prevalence of molecular diagnoses in dilated cardiomyopathy patients within a real-world clinical setting using whole exome sequencing and evidence-based variant curation.
Conducted whole exome sequencing in 83 eligible patients with idiopathic or familial dilated cardiomyopathy.
Prioritized and curated variants across up to 247 genes using American College of Medical Genetics and Genomics (ACMG) classification guidelines.
Pathogenic or likely pathogenic variants were detected in 12% (10/83) of participants across 8 tier 1 genes, including 2 genes omitted from standard commercial gene panels.
Truncating TTN variants of uncertain significance were present in 10% (8/83) of patients, while 6% (5/83) had variants classified as uncertain under ACMG criteria despite external lab classifications of pathogenic or likely pathogenic.
The bioinformatics pipeline produced an average of 0.74 variants of uncertain significance per case, requiring approximately 0.75 person-hours for curation per variant.

Study Design

Type

Observational (n=83)

Multicenter

Yes

PICO

P

Population

83 probands with idiopathic or familial dilated cardiomyopathy prospectively underwent whole exome sequencing alongside routine clinical care, followed for a median of 501 days.

E

Exposure / Comparator

Whole exome sequencing

O

Primary Outcome

Proportion of patients with a pathogenic or likely pathogenic variant

Limitations

First- and second-degree relatives were not comprehensively investigated, which may have led to underrecognition of family history.
Whole exome sequencing has limited sensitivity for detecting large insertion/deletion variants, copy number variations, translocations, and repeat expansions.
Potential missing variants due to variability in the breadth of coverage involving certain genes and low mappability of certain sarcomeric genes.

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Implication

Supports cautious ACMG-based variant interpretation in dilated cardiomyopathy testing; challenges prior higher detection rates and leaves optimal panels open for validation.

Abstract

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Cite This Study

Zhang et al. (2023) conducted an observational in Dilated cardiomyopathy (n=83). Whole exome sequencing was evaluated on Proportion of patients with a pathogenic or likely pathogenic variant. Whole exome sequencing identified a pathogenic or likely pathogenic variant in 12% of patients with dilated cardiomyopathy using stringent American College of Medical Genetics and Genomics criteria.

synapsesocial.com/papers/6acdb7923babf208a60f954f https://doi.org/10.12998/wjcc.v11.i11.2412

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Study of pathogenic genes in a pedigree with familial dilated cardiomyopathy

Key Points

Study Design

PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Study of pathogenic genes in a pedigree with familial dilated cardiomyopathy

Key Points

Study Design

PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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