A Novel Deep‐Intronic Variant in
HES7
Unveils a Poison Exon Mechanism Underlying Spondylocostal Dysostosis
Elsa Lucas‐Castro, Mercedes León‐López, Alejandra Ráez‐Casarrubios, Francisca Díaz‐González, Silvia Modamio‐Høybjør, Ana Coral Barreda‐Bonis, Emi Rikeros‐Orozco, Pablo Lapunzina, Fernando Santos‐Simarro, Manuel Parrón‐Pajares, Karen E. Heath 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.