ArticleGenetics in medicine : official journal of the American College of Medical Genetics2024
Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Cell modeling and rescue of a novel noncoding genetic cause of glycogen storage disease IX.Genetics in medicine open · 2026Article
- Beyond the Exome: The Role of Noncoding and Regulatory Variants in Monogenic Diseases.Current issues in molecular biology · 2025Review
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease.Genome medicine · 2025Article
- Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S.Molecular therapy. Nucleic acids · 2025Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
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15 authors.
Funding
Abstract
purposeIdentifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding "second hits" in trans with these is unknown.
methodsIn 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare noncoding variants on the other haplotype in introns, untranslated regions, promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit and performed functional testing where possible.
resultsWe identified 3761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2430 probands. For 1366 (36.3%) of these, we identified at least 1 rare noncoding variant in trans. Bioinformatic filtering and clinical review, revealed 7 to be a good clinical fit. After detailed characterization, we identified likely diagnoses for 3 probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further 3 (PAH, LAMA2, and IGHMBP2).
conclusionWe developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/noncoding variants and conclude that this mechanism is likely to be a rare cause of DDs.
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