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Clinical genetic testing of protein-coding regions identifies a likely causative variant in only [~]35% of severe developmental disorder (DD) cases. We screened 9,858 patients from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5untranslated regions (5UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream of MEF2C that cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding variants represent 23% of disease-causing variants identified in MEF2C in the DDD cohort. Our analyses show that non-coding variants upstream of known disease-causing genes are an important cause of severe disease and demonstrate that analysing 5UTRs can increase diagnostic yield, even using existing exome sequencing datasets. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants, and dosage tolerance of the gene.

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