Rare disease gene

Rare disease gene association discovery in the 100,000 Genomes Project

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, with many probably involving pathogenic variants in yet to be discovered disease–gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project2. A total of 141 new associations were identified, including five for which independent disease–gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence.

The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4 UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot–Marie–Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease–gene association discovery.

Rare diseases collectively affect 3.5% to 5.9% of people worldwide5. Despite advances in genomic sequencing, molecular diagnosis continues to elude 50% to 80% of patients presenting to genetic clinics1. Furthermore, fewer than half of the 10,000 rare Mendelian diseases in the Online Mendelian Inheritance in Man (OMIM) database6 have an established genetic basis. Diagnostic failure may arise because of a lack of routine screening for non-coding7 or structural variants1. However, it is likely that a substantial proportion of the pathogenic variants responsible for patients undiagnosed with rare disease (cases) reside in those yet to be discovered genes associated with (possibly very rare) disorders.

The scale of rare disease sequencing studies, such as the Undiagnosed Disease Network8, Centers for Mendelian Genomics9, Deciphering Developmental Disorders10 and the 100,000 Genomes Project (100KGP)2, offers expanded opportunities to provide insight into pathogenic mechanisms of inherited disease, including the possibility of establishing disease–gene associations through case–control analyses, akin to methods used previously to identify common genetic variants influencing the risk of complex disorders. Such an approach provides much-needed power to identify genes harbouring rare pathogenic variants.

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