RNA sequencing resolves novel DYNC2H1 variants causing short‐rib thoracic dysplasia type 3: Case report

BACKGROUND: Intronic variants outside the canonical splice site are challenging to interpret and therefore likely represent an underreported cause of human disease. Autosomal recessive variants in DYNC2H1 are associated with short‐rib thoracic dysplasia 3 with or without polydactyly (SRTD3), a clinically heterogeneous disease generally presenting with short ribs, shortened tubular bones, narrow thorax and acetabular roof anomalies. We describe a case of SRTD3 with compound heterozygous frameshift and intronic variants and highlight the essential role of RNA sequencing (RNA‐Seq) in variant interpretation. METHODS: Following inconclusive clinical genetic testing identifying a likely pathogenic frameshift variant and an intronic variant of uncertain significance (VUS) in DYNC2H1 in trans, the family enrolled in the Care4Rare Canada research program, where RNA‐Seq studies were performed. RESULTS: The proband presented with post‐axial polydactyly of all four limbs, a significantly small chest with a pectus excavatum and anterior flaring of the ribs. RNA‐Seq investigations revealed a novel splice junction as a result of the intronic VUS and significantly decreased DYNC2H1 gene expression in the proband. CONCLUSION: This case demonstrates the diagnostic utility of RNA‐Seq for variant interpretation following inconclusive clinical testing, which can ultimately lead to diagnosis for patients with rare disease.