英国惠康桑格研究所Hilary C. Martin团队近期取得重要工作进展，他们对来自不同人群29745名发育障碍患者的，常染色体隐性编码变异进行联合分析。相关研究成果2024年9月23日在线发表于《自然—遗传学》杂志上。

据介绍，常染色体隐性编码变异是罕见疾病常见原因。

研究人员在一个由29745个三人组构成的大型、血统多样的队列中量化了这些变异对发育障碍的贡献，其中20.4%的人有非欧洲血统的遗传推断。在遗传推断的祖先群体中，可归因于外显子组范围常染色体隐性编码变异的患者比例估计在~2-19%之间，与平均自交性显著相关。

已建立的常染色体隐性发育障碍相关（ARDD）基因解释了总常染色体隐性编码负担的84.0%，这些已建立基因中34.4%的负担是由尚未在ClinVar中报告为致病性的变异解释的。统计分析确定了两个新的ARDD基因：KBTBD2和ZDHHC16。

总之，这一研究扩展了人们对不同遗传推断祖先群体发育障碍遗传结构的理解，并表明改进解释已知ARDD基因错义变异的策略可能有助于诊断更多的患者，而不是发现剩余的基因。

附：英文原文

Title: Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations

Author: Chundru, V. Kartik, Zhang, Zhancheng, Walter, Klaudia, Lindsay, Sarah J., Danecek, Petr, Eberhardt, Ruth Y., Gardner, Eugene J., Malawsky, Daniel S., Wigdor, Emilie M., Torene, Rebecca, Retterer, Kyle, Wright, Caroline F., lafsdttir, Hildur, Guillen Sacoto, Maria J., Ayaz, Akif, Akbeyaz, Ismail Hakki, Trkdoan, Dilad, Al Balushi, Aaisha Ibrahim, Bertoli-Avella, Aida, Bauer, Peter, Szenker-Ravi, Emmanuelle, Reversade, Bruno, McWalter, Kirsty, Sheridan, Eamonn, Firth, Helen V., Hurles, Matthew E., Samocha, Kaitlin E., Ustach, Vincent D., Martin, Hilary C.

Issue&Volume: 2024-09-23

Abstract: Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2–19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes.

DOI: 10.1038/s41588-024-01910-8

Source: https://www.nature.com/articles/s41588-024-01910-8