What is the clinical evidence from this study?

Study design: Observational. Population: Dilated cardiomyopathy undergoing heart transplantation (n=776). Intervention: Whole-exome sequencing vs. Reference group without cardiomyopathy. Primary outcome: Enrichment of titin (TTN) truncating variants (p=1.66E-15).

What does this research mean for the field?

Titin (TTN) and filamin C (FLNC) truncating variants are significantly enriched in Chinese patients with dilated cardiomyopathy undergoing heart transplantation, with FLNC truncation associated with more severe clinical symptoms. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

July 17, 2023Open Access

Genetic characterization of dilated cardiomyopathy patients undergoing heart transplantation in the Chinese population by whole-exome sequencing

HLHong LianChinese Academy of Medical Sciences & Peking Union Medical College SSShen SongChinese Academy of Medical Sciences & Peking Union Medical College WCWenzheng ChenPeking University

Key Result

Whole-exome sequencing revealed that titin (TTN) and filamin C (FLNC) truncating variants were significantly enriched in Chinese patients with dilated cardiomyopathy undergoing heart transplantation.

Study Design

Type

Observational (n=776)

Multicenter

Structured PICO

Population

208 unrelated Chinese patients with dilated cardiomyopathy (DCM) who underwent heart transplantation (HTx) due to end-stage heart failure (NYHA III-IV, mean LVEF 23.9%), mean age of HTx 42.4 years, 80.3% male.

Intervention

Whole-exome sequencing (WES)

Comparator

568 reference subjects (187 obese children without cardiac defects and 381 patients with transposition of the great arteries)

Outcome

Enrichment of rare protein-altering variants (gene burden analysis) and variant classificationsurrogate

Whole-exome sequencing reveals that TTN and FLNC truncating variants are the most common genetic causes of end-stage dilated cardiomyopathy requiring heart transplantation in the Chinese population, with FLNC variants associated with severe clinical symptoms.

Main Result

Absolute Event Rate: 18.8% vs 1.9%

p-value: p=1.66E-15

Limitations

Utilizing published data as a reference population dataset presents inherent limitations, including unknown prevalence of DCM and different exon capture kits.
Survival bias may result in cohorts being depleted of variants that cause severe early-onset DCM.
Investigation centered on variants within protein-coding regions, missing noncoding, epigenetic, and large structural variants.
The number of patients enrolled was relatively low, and no replication cohort was provided.

Abstract

BACKGROUND: Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx remains to be further studied. This study aimed to characterize the genetic basis of DCM HTx in the Chinese population. METHODS: In total, 208 unrelated DCM patients who underwent HTx at Fuwai Hospital between June 2004 and June 2017 were included in this study. Whole-exome sequencing (WES) was performed for all patients. Gene burden analysis, variant classification, and genotype-phenotype correlation analysis were subsequently performed. RESULTS: After completing the bioinformatics analysis, gene burden analysis suggested that titin (TTN), filamin C (FLNC) and lamin A/C (LMNA) were significantly enriched with rare protein-altering variants. The frequencies of TTN and FLNC truncating variants in our cohort were 18.8% and 8.7%, respectively. Among the 165 rare variants in high evidence DCM-related genes, 27 (16.4%) and 59 (35.8%) were interpreted as pathogenic (P) and likely pathogenic (LP), respectively. In addition, 41 (47.7%) and 16 (18.6%) of these 86 P/LP variants are located in TTN and FLNC, respectively. The FLNC group contained more patients with NYHA class IV than the P/LP-negative group (FLNC, 16/18 vs. P/LP-negative, 81/123, P = 0.049). CONCLUSIONS: Based on WES, we provided a primary genetic spectrum of DCM patients undergoing HTx in the Chinese population. TTN and FLNC harbour the most P/LP variants. FLNC truncation may lead to severe clinical symptoms in DCM patients.

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