Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms
File(s)MEF2Cmanuscript_merged.pdf (1.5 MB)
Accepted version
Author(s)
Type
Journal Article
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 distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. 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.
Date Issued
2021-06-03
Online Publication Date
2021-11-20T00:02:12Z
Date Acceptance
2021-04-29
ISSN
0002-9297
Publisher
Cell Press
Start Page
1083
End Page
1094
Journal / Book Title
American Journal of Human Genetics
Volume
108
Issue
6
Copyright Statement
© 2021 American Society of Human Genetics. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Leducq Foundation for Cardiovascular Research
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34022131
S0002-9297(21)00184-1
Grant Number
16CVD03
RDB02
Subjects
developmental disorders, clinical genetic testing, non-coding region variants, 5' UTR variants
Genomics England Research Consortium
developmental disorders, clinical genetic testing, non-coding region variants, 5' UTR variants
Genetics & Heredity
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Country
United States
Date Publish Online
2021-05-21