PDF(Pubmed)
Abstract：
Cardiomyopathies are a leading cause of progressive heart failure and sudden cardiac death; however, their genetic aetiology remains poorly understood. We hypothesised that variants in noncoding regulatory regions and oligogenic inheritance mechanisms may help close the diagnostic gap.
We first analysed whole-genome sequencing data of 143 parent-offspring trios from Genomics England 100,000 Genomes Project. We used gene panel testing and a phenotype-based, variant prioritisation framework called Exomiser to identify candidate genes in trios. To assess the contribution of noncoding DNVs to cardiomyopathies, we intersected DNVs with open chromatin sequences from single-cell ATAC-seq data of cardiomyocytes. We also performed a case-control analysis in an exome-negative cohort, including 843 probands and 19,467 controls, to assess the association between noncoding variants in known cardiomyopathy genes and disease.
In the trio analysis, a definite or probable genetic diagnosis was identified in 21 probands according to the American College of Medical Genetics guidelines. We identified novel DNVs in diagnostic-grade genes (RYR2, TNNT2, PTPN11, MYH7, LZR1, NKX2-5), and five cases harbouring a combination of prioritised variants, suggesting that oligogenic inheritance and genetic modifiers contribute to cardiomyopathies. Phenotype-based ranking of candidate genes identified in noncoding DNV analysis revealed JPH2 as the top candidate. Moreover, a case-control analysis revealed an enrichment of rare noncoding variants in regulatory elements of cardiomyopathy genes (p = .035, OR = 1.43, 95% Cl = 1.095-1.767) versus controls. Of the 25 variants associated with disease (p< 0.5), 23 are novel and nine are predicted to disrupt transcription factor binding motifs.
Our results highlight complex genetic mechanisms in cardiomyopathies and reveal novel genes for future investigations.
We first analysed whole-genome sequencing data of 143 parent-offspring trios from Genomics England 100,000 Genomes Project. We used gene panel testing and a phenotype-based, variant prioritisation framework called Exomiser to identify candidate genes in trios. To assess the contribution of noncoding DNVs to cardiomyopathies, we intersected DNVs with open chromatin sequences from single-cell ATAC-seq data of cardiomyocytes. We also performed a case-control analysis in an exome-negative cohort, including 843 probands and 19,467 controls, to assess the association between noncoding variants in known cardiomyopathy genes and disease.
In the trio analysis, a definite or probable genetic diagnosis was identified in 21 probands according to the American College of Medical Genetics guidelines. We identified novel DNVs in diagnostic-grade genes (RYR2, TNNT2, PTPN11, MYH7, LZR1, NKX2-5), and five cases harbouring a combination of prioritised variants, suggesting that oligogenic inheritance and genetic modifiers contribute to cardiomyopathies. Phenotype-based ranking of candidate genes identified in noncoding DNV analysis revealed JPH2 as the top candidate. Moreover, a case-control analysis revealed an enrichment of rare noncoding variants in regulatory elements of cardiomyopathy genes (p = .035, OR = 1.43, 95% Cl = 1.095-1.767) versus controls. Of the 25 variants associated with disease (p< 0.5), 23 are novel and nine are predicted to disrupt transcription factor binding motifs.
Our results highlight complex genetic mechanisms in cardiomyopathies and reveal novel genes for future investigations.
摘要：
心肌病是进行性心力衰竭和心源性猝死的主要原因;然而,他们的遗传病因仍然知之甚少。我们假设非编码调节区的变异和寡基因遗传机制可能有助于缩小诊断差距。
我们首先分析了来自GenomicsEngland100,000基因组计划的143个亲代后代三重奏的全基因组测序数据。我们使用基因面板测试和基于表型的，称为Exomiser的变体优先级框架，用于识别三重奏中的候选基因。为了评估非编码DNV对心肌病的贡献，我们从心肌细胞的单细胞ATAC-seq数据中将DNV与开放染色质序列相交。我们还在外显子组阴性队列中进行了病例对照分析，包括843个先证者和19,467个控制者，评估已知心肌病基因中的非编码变异与疾病之间的关联。
在三重奏分析中,根据美国医学遗传学学会指南,在21名先证者中确定了明确或可能的基因诊断.我们在诊断级基因（RYR2，TNNT2，PTPN11，MYH7，LZR1，NKX2-5）中鉴定了新的DNV，五个案例包含优先变体的组合，表明寡基因遗传和遗传修饰有助于心肌病。在非编码DNV分析中鉴定的候选基因的基于表型的排序显示JPH2是最佳候选基因。此外，病例对照分析显示,与对照组相比,心肌病基因调控元件中罕见的非编码变异体富集(p=.035,OR=1.43,95%Cl=1.095-1.767).在与疾病相关的25种变异中(p<0.5)，23个是新的,并且预测9个破坏转录因子结合基序。
我们的研究结果强调了心肌病的复杂遗传机制，并揭示了未来研究的新基因。
我们首先分析了来自GenomicsEngland100,000基因组计划的143个亲代后代三重奏的全基因组测序数据。我们使用基因面板测试和基于表型的，称为Exomiser的变体优先级框架，用于识别三重奏中的候选基因。为了评估非编码DNV对心肌病的贡献，我们从心肌细胞的单细胞ATAC-seq数据中将DNV与开放染色质序列相交。我们还在外显子组阴性队列中进行了病例对照分析，包括843个先证者和19,467个控制者，评估已知心肌病基因中的非编码变异与疾病之间的关联。
在三重奏分析中,根据美国医学遗传学学会指南,在21名先证者中确定了明确或可能的基因诊断.我们在诊断级基因（RYR2，TNNT2，PTPN11，MYH7，LZR1，NKX2-5）中鉴定了新的DNV，五个案例包含优先变体的组合，表明寡基因遗传和遗传修饰有助于心肌病。在非编码DNV分析中鉴定的候选基因的基于表型的排序显示JPH2是最佳候选基因。此外，病例对照分析显示,与对照组相比,心肌病基因调控元件中罕见的非编码变异体富集(p=.035,OR=1.43,95%Cl=1.095-1.767).在与疾病相关的25种变异中(p<0.5)，23个是新的,并且预测9个破坏转录因子结合基序。
我们的研究结果强调了心肌病的复杂遗传机制，并揭示了未来研究的新基因。
