Phenotypic heterogeneity inDYNC2H1-related short-rib thoracic dysplasia: antenatal indicators and postnatal outcomes

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