Phenogenon: Gene to phenotype associations for rare genetic diseases

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon on our cohort of 3,290 patients who had undergone whole exome sequencing. Among the top associations, we recapitulated previously known, such as "SRD5A3—Abnormal full-field electroretinogram—recessive" and "GRHL2 –Nail dystrophy—recessive", and discovered one potentially novel, “RRAGA–Abnormality of the skin—dominant”. We also developed an interactive web interface available at https://phenogenon.phenopolis.org to visualise and explore the results.

随着高通量测序（High-throughput sequencing）愈发广泛地应用于罕见孟德尔遗传病的分子诊断，大量携带多样表型的患者的遗传与表型数据被汇集整合，以挖掘全新的基因-表型关联。我们在此推出Phenogenon：一款整合了经人类表型本体（Human Phenotype Ontology, HPO）注释的患者表型数据、基因组聚合数据库（gnomAD）等位基因人群频率，以及用于评估变异致病性的联合注释依赖剔除（Combined Annotation Dependent Depletion, CADD）评分的统计工具，可联合预测遗传模式与基因-表型关联。我们将Phenogenon应用于3290名接受全外显子组测序（whole exome sequencing）的患者队列开展分析。在所得的高置信度关联结果中，我们验证了多项已报道的关联，例如"SRD5A3—异常全视野视网膜电图—隐性遗传"与"GRHL2—甲营养不良—隐性遗传"，同时发现了一条潜在的新型关联："RRAGA—皮肤异常—显性遗传"。此外，我们还开发了交互式网页界面，可通过https://phenogenon.phenopolis.org访问，用于可视化展示与探索本次分析的结果。