Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.

ABSTRACT: Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three dis

SUBMITTER: Wright CF 

PROVIDER: S-EPMC8206381 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature