Genotype‐Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy

Abstract

Background Left ventricular noncompaction cardiomyopathy ( LVNC ) is a genetically and phenotypically heterogeneous disease. This study aims to investigate the genetic basis and genotype‐phenotype correlations in a cohort of Chinese patients with LVNC . Methods and Results A total of 72 cardiomyopathy‐associated genes were comprehensively screened in 83 adults and 17 children with LVNC by targeted sequencing. Pathogenicity of the detected variants was determined according to their prevalence and American College of Medical Genetics and Genomics recommendations. Baseline and follow‐up clinical data were collected. The primary end point was a composite of death and heart transplantation. Overall, 42 pathogenic variants were identified in 38 patients (38%), with TTN , MYH 7 , MYBPC 3 , and DSP being the most commonly involved genes. At baseline, genotype‐positive adults had higher rates of atrial fibrillation and family history, and lower left ventricular ejection fraction, compared with genotype‐negative adults. During a median follow‐up of 4.2 years, more primary end points occurred in genotype‐positive adults than in genotype‐negative adults (50.0% versus 23.5%; P =0.013). Multivariable analysis demonstrated that genotype‐positive status was associated with higher risks of death and heart transplantation, independent of age, sex, and cardiac function at baseline in patients with LVNC (adjusted hazards ratio, 2.49; 95% confidence interval, 1.15–5.37; P =0.020). Conclusions Our study revealed a distinct genetic spectrum in Chinese patients with LVNC , with variants in TTN , MYH 7 , MYBPC 3 , and DSP being the most common. The presence of pathogenic variants is an independent risk factor for adverse outcomes and may aid in risk stratification in adult patients. Larger studies are needed to confirm these findings.

Left ventricular noncompaction − Risk stratification and genetic consideration −

“…Although there are an increasing number of reports describing genotype-phenotype correlations, genotype-phenotype correlations have been challenging. These reports of LVNC cohorts have been showing varying and often conflicting results [22][23][24][25][26][27]56]. A recent multicenter study analyzed 327 unrelated pediatric (n = 52) and adult (n = 275) patients with LVNC whose disease was categorized: (1) genetic (mutation positive), (2) probably genetic (mutation negative, family history positive), and (3) sporadic (mutation negative, family history negative) [22].…”

“…Li et al report their single-center genotype-phenotype correlations in Chinese patients with LVNC. A total of 72 cardiomyopathy-associated genes were comprehensively screened in 83 adults and 17 children with LVNC by targeted sequencing [24]. Overall, 42 pathogenic variants were identified in 38 patients (38%), with TTN, MYH7, MYBPC3, and DSP being the most commonly involved genes.…”

“…3) [21]. Although there are an increasing number of reports describing genotype-phenotype correlations, genotype-phenotype correlations have been challenging and risk stratification is an ongoing investigation [22][23][24][25][26][27]. Given that 20-40% of cases may be familial, family screening is recommended when the diagnosis of LVNC is made in a child [9].…”

Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes

“…In a large cohort of 327 noncompaction cardiomyopathy including 52 children and 275 adults, the authors identified a higher prevalence of multiple hits in children (10%) than in adults (3%) ( p = .038) (van Waning et al, ). In another cohort of 100 patients, 6/83 adults were carriers of multiple variants (7%), and 1/17 children (5%) (Li et al, ). Further studies are necessary to clarify the prevalence of multiple hits in LVNC.…”

Clinical implications of sarcomere and nonsarcomere gene variants in patients with left ventricular noncompaction cardiomyopathy

“…Patients enrollment, genetic sequencing, variant classification, and follow‐up have been described in a previous study. (Li et al, ) Briefly, the diagnosis of LVNC was based on echocardiographic or cardiac magnetic resonance findings according to Jenni et al or Petersen et al criteria. (Jenni, Oechslin, Schneider, Attenhofer Jost, & Kaufmann, ; Petersen et al, ) Patients were eligible if they had LVNC and were willing to receive genetic testing and follow‐up.…”