Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 108, Issue 6, Pages 1083-1094Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2021.04.025
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Funding
- Sir Henry Dale Fellowship - Wellcome Trust [220134/Z/20/Z]
- Sir Henry Dale Fellowship - Royal Society [220134/Z/20/Z]
- Rosetrees and Stoneygate Imperial College Research Fellowship
- Imperial College Academic Health Science Centre
- Rosetrees Trust [H5R01320]
- Wellcome Trust [WT200990/Z/16/Z, WT200990/A/16/Z, HICF-1009-003]
- Fondation Leducq [16 CVD03]
- National Institute forHealth Research (NIHR) Imperial College Biomedical Research Centre
- Cardiovascular Research Centre
- Royal Brompton & Harefield NHS Trust
- NIHR Oxford Biomedical Research Centre Programme
- Department of Health [HICF-1009-003]
- Wellcome Trust Sanger Institute [WT098051]
- National Institute for Health Research
- NHS England
- Cancer ResearchUK
- Medical Research Council
- Wellcome
- Wellcome Trust
- Wellcome Trust [220134/Z/20/Z] Funding Source: Wellcome Trust
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This study highlights the significant role of non-coding region variants in the diagnosis of developmental disorders, particularly through various loss-of-function mechanisms. These variants may be overlooked in traditional clinical genetics approaches, but are easily detectable through exome sequence data.
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.
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