Expanding the genetic spectrum of short rib polydactyly syndrome: Novel DYNC2H1 variants and functional insights

Short rib polydactyly syndrome (SRPS), with or without polydactyly, also known as Verma-Naumoff/Saldino-Noonan syndrome, is a type of skeletal ciliopathy. Initially, variants in the IFT80 gene were implicated; however, approximately half of the SRPS cases are associated with variants in the DYNC2H1 gene. Additionally, digenic variants involving DYNC2H1 and NEK1 can contribute to the syndrome.

This case report describes a male patient presenting with characteristic SRPS features, including a constricted thorax and shortened limbs. Exome sequencing was performed to identify causative variants, followed by functional analyses to assess the pathogenicity of the identified variants, including a synonymous variant.

Exome sequencing identified compound heterozygous variants in the DYNC2H1 gene: a novel missense variant c.6439G>T p.(Asp2147Tyr) and a synonymous variant c.6477G>A p.(Gln2159=). Functional analyses confirmed that the synonymous variant triggers nonsense-mediated decay of the affected allele.

This study expands the spectrum of DYNC2H1 variants associated with SRPS and emphasizes the importance of functional analyses in genetic diagnostics. Demonstrating pathogenicity for a synonymous variant highlights the necessity for comprehensive variant assessments to improve diagnostic accuracy and enable early intervention. These findings have significant implications for molecular diagnostics and personalized therapy strategies in skeletal ciliopathies.