[Compound heterozygous DYNC2LI1 variants causing short-rib thoracic dysplasia 15 with polydactyly]

Pathogenic variants in the DYNC2LI1 gene are associated with autosomal recessive short-rib thoracic dysplasia 15 (SRTD15), a ciliopathy characterized by skeletal abnormalities with or without polydactyly. The gene encodes a component of the dynein-2 complex essential for retrograde intraflagellar transport and proper ciliary function. We present the case of a newborn child with a primarily skeletal developmental disorder and identify the causative variants. Whole exome sequencing was performed on the DNA of the proband with multiple congenital anomalies. The presence of the identified variants in the parents' DNA was tested by Sanger sequencing. The newborn proband presented with polydactyly affecting all four limbs, syndactyly of the toes, narrow thorax with short ribs, minor cleft lip, and incomplete development of the dental alveolar ridge. Whole exome sequencing identified two pathogenic variants in DYNC2LI1: c.659C>T (p.Thr220Ile) and c.731+1G>T, confirmed to be in trans by Sanger sequencing of the parental DNA. Both variants were classified as pathogenic based on the American College of Medical Genetics / Association for Clinical Genomic Science criteria. The missense variant affects a conserved residue within the nucleoside triphosphate hydrolase domain and has been previously functionally validated, while the splice-site variant is predicted to result in loss of function. This genetically first described SRTD case in Hungary expands the mutational and phenotypic spectrum of DYNC2LI1-related ciliopathies. The identified compound heterozygous variants are the most consistent with the clinical diagnosis of SRTD15. The distinction among SRTD disorders is often impossible solely on clinical bases. The pathogenic DYNC2LI1 variants are also associated with a known clinical spectrum of allelic disorders. Our findings highlight the importance of whole exome sequencing in diagnosing the genetically heterogeneous skeletal dysplasias, and support the role of DYNC2LI1 dysfunction in impaired ciliary transport and skeletal development. Orv Hetil. 2026; 167(43): 1749-1755.