P3.238 Generating Evidence Through Serosurveillance; Helping in Programme Designing to Mitigate Sexually Transmitted Infections (STIs) Among Female Sex Workers (FSWs) in Bangladesh

Abstract

<h3>Abstract</h3> 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 <i>de novo</i> mutations in the 5’untranslated regions (5’UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream of <i>MEF2C</i> 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 <i>MEF2C</i> 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 5’UTRs 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.