Phenotypic heterogeneity in DYNC2H1-related short-rib thoracic dysplasia: antenatal indicators and postnatal outcomes.

Introduction: DYNC2H1-related short-rib thoracic dysplasia with/without polydactyly (SRTD), formerly asphyxiating thoracic dystrophy-Jeune syndrome, is a rare genetic skeletal disorder characterised by a narrow thorax, short ribs, shortened long bones and brachydactyly/polydactyly. DYNC2H1-related SRTD shows significant phenotypic variability. There is limited information regarding correlations between genotypes, antenatal ultrasound findings and clinical phenotypes and severity.

Methods: A retrospective study of confirmed DYNC2H1-related SRTD cases was conducted through paper and digital medical records. Data collected included patient demographics, initial presentation, postnatal progression, childhood follow-up, antenatal ultrasound imaging, postnatal skeletal surveys and genetic variant analysis.

Results: Nine individuals from eight families across three tertiary genetic centres in England were included in the study. Eight presented in the antenatal period (gestation 14-36 weeks) and one in the postnatal period at 6 weeks. All nine displayed a narrow thorax and eight displayed shortened long bones (humerus and/or femur). Polydactyly was less common and seen in only four individuals. Phenotypic severity was variable, including mild (n=4), moderate requiring respiratory support (n=2) and severe/lethal (n=3) cases. Earlier antenatal presentation and more significant femur shortening and bowing were predictive of poor postnatal prognosis, and there were no clear genotype-phenotype correlations. We also report seven novel DYNC2H1 variants, not previously reported.

Conclusion: DYNC2H1-related SRTD exhibits significant phenotypic variability which cannot be reliably predicted by genotype but has some correlation with time of gestational presentation.