Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants

Purpose: Identifying 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. Methods: In 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 fi t and performed functional testing where possible. Results: We 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 fi ltering and clinical review, revealed 7 to be a good clinical fi t. 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). Conclusion: We 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. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).