A Novel Deep‐Intronic Variant in HES7 Unveils a Poison Exon Mechanism Underlying Spondylocostal Dysostosis

ABSTRACT Spondylocostal dysostosis is an ultra‐rare disorder caused by pathogenic variants in seven genes including HES7 . To date, only 13 probands and seven causative variants have been identified, all affecting coding or canonical or proximal splicing regions. Here we report a girl with spondylocostal dysostosis in whom no molecular cause had been identified in these genes by exome trio analysis. After performing whole genome sequencing, a novel deep‐intronic homozygous variant was identified in HES7 . Splicing assays demonstrated that the variant results in increased aberrant alternative exon inclusion resulting in the introduction of a premature termination codon, likely targeting aberrant transcripts for degradation via nonsense‐mediated decay. Interestingly, such aberrant exon inclusion occurs at low levels in healthy individuals, in a tissue‐dependent manner, suggesting an underlying physiological role as a poison exon.