Genetic association analysis of 269 rare diseases reveals novel aetiologies

The genetic aetiologies of more than half of rare diseases remain unknown 1 . Standardised genome sequencing (GS) and phenotyping of large patient cohorts provides an opportunity for discovering the unknown aetiologies 2 , but this depends on efficient and powerful analytical methods 3 . We have developed a portable computational and statistical framework for inferring genetic associations with rare diseases. At its core lies the ‘Rareservoir’, a compact database of rare variant genotypes and phenotypes. We built a Rareservoir of 77,539 genomes sequenced by the 100,000 Genomes Project (100KGP) 4 . We then applied the Bayesian association method, BeviMed 3 , across 269 rare diseases assigned to participants in the project, identifying 238 known 5 and 21 novel associations. The novel results included three which we selected for validation. We provide compelling evidence that (1) loss-of-function variants in the ETS-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of TGFβ regulator PMEPA1 result in Loeys-Dietz syndrome 6 , and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. These novel findings confirm the power of our analytical approach for the aetiological discovery of rare diseases.