National Heart and Lung Institute, Imperial College London, London, UK.
Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Genome Med. 2024 Oct 29;16(1):125. doi: 10.1186/s13073-024-01390-9.
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.
心肌病是具有重要临床意义的疾病，具有很强的遗传成分。国家基因组计划，如 10 万基因组计划（100KGP），为研究这些罕见疾病提供了机会，可以在常规研究之外进行大规模研究。
我们介绍了 100KGP 队列的临床和分子特征，比较了具有不同心肌病的儿科和成年先证者。我们评估了不同临床表现下遗传病因的诊断率和谱。我们使用更新的分析策略（修订后的基因面板；对新生变异的无偏分析；以及改进的变异优先级策略）重新分析了现有基因组数据，以鉴定新的遗传未解决儿童中的致病变异。
我们在 100KGP 中鉴定了 1918 名（1563 名先证者，355 名亲属）患有心肌病（CM）的个体。先证者包括 273 名儿童和 1290 名成人，根据 55 种以上不同的招募类别进行了招募。与成人（0.9%）相比，儿科先证者更常伴有先天性心脏病（12%）。100KGP 初始分析后，儿童的诊断率（19%）明显高于成人（11%），总体诊断率中有 11%是在现有的英国儿科或综合征性 CM 面板之外的基因中做出的。我们对儿科先证者的重新分析得出了 40%的潜在诊断结果，在 49 例以前未解决的儿科病例中确定了新的可能或可能的诊断。结构性和内含子变异占儿童所有潜在诊断的 11%，而新生变异占 17%。
100KGP 表明，在 CM 中，全基因组测序比单独使用面板更有优势。对儿科 CM 先证者的重新分析显著提高了诊断率，强调了在基因组研究中反复评估的重要性。尽管做出了这些努力，但许多患有 CM 的儿童仍未得到遗传诊断，这突出表明需要更好地进行基因-疾病关系的整理和持续的数据共享。100KGP 的 CM 队列可能对进一步的基因发现有用，但必须理解和解决异质确定和关键技术限制。
