ArticleAmerican journal of human genetics2021
Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 76 citations in OpenAlex.
- A nationwide prospective randomized trial for diagnosing developmental disorders demonstrates genome sequencing outperforms standard of care.Genome medicine · 2026Trial
- Genetic architecture of white matter microstructure captured by unsupervised deep representation learning of fractional anisotropy maps.Nature communications · 2026Article
- Identification of 5' untranslated region variants in genes involved in neurodevelopmental disorders.Journal of human genetics · 2026Article
- Genome-wide detection of human 5' UTR variants that impact protein translation.American journal of human genetics · 2026Article
- PKD1 5'UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development.European journal of human genetics : EJHG · 2026Article
- Identification of an episignature for the MEF2C-associated syndrome.European journal of human genetics : EJHG · 2026Article
- Approaches for identification of 5' UTR mutations impacting translation and protein production from neurodevelopmental disorder genes.Cell reports methods · 2025Article
- Genetic Mechanisms of Experience-Dependent Neuronal Plasticity.Annual review of genetics · 2025Review
- A human YEATS4 variant confers resistance to TST and IGRA conversion despite Mycobacterium tuberculosis exposure.Genome medicine · 2025Article
- uAUG-creating variant in the LDLR gene causes mild Familial hypercholesterolemia.Human genetics · 2025Article
- Unveiling genetic architecture of white matter microstructure through unsupervised deep representation learning of fractional anisotropy maps.Research square · 2025Article
- The role of untranslated region variants in Mendelian disease: a review.European journal of human genetics : EJHG · 2025Review
- Genetic variants in the CD59 gene: An exploratory study of large genome databases.Transfusion · 2025Article
- Hidden in the Genome: The First Italian Family with North Carolina Macular Dystrophy Carrying a NovelBiomedicines · 2025Article
- Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease.Genome medicine · 2025Article
- LMX1B haploinsufficiency due to variants in the 5'UTR as a cause of Nail-Patella syndrome.NPJ genomic medicine · 2025Article
- Systematic identification of pathogenic variants of non-small cell lung cancer in the promoters of DNA-damage repair genes.EBioMedicine · 2024Article
- Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- LNC-ing Genetics in Mitochondrial Disease.Non-coding RNA · 2024Article
- Upstream open reading frame-introducing variants in patients with primary familial brain calcification.European journal of human genetics : EJHG · 2024Article
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Authors and funding
34 authors at 18 institutions in 4 countries.
Funding
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.
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