To analyze pathogenic variations and phenotypes in male and female participants with ZC4H2-Associated Rare Disorder (ZARD)

ZARD is a rare condition caused by a pathogenic variation of the ZC4H2 gene on the X-chromosome. This gene codes for a zinc-finger protein important in nervous system development. ZARD is characterized by variable symptoms, potentially influenced by a patient’s sex. In this study, we analyze data gathered from visits with 40 participants (0-21 years old), the largest ZARD cohort studied thus far.

This is a prospective natural history study. Parents were interviewed about their child’s symptoms and development. We also conducted physical and neurological examinations. The features prevalent in participants were compared by sex. Fisher’s exact, maximum likelihood χ2, and Mann-Whitney tests were utilized.

Males tended to have maternally-inherited variations, while females tended to have de novo variations (p<0.001). Male participants were more likely to have seizures (p<0.1), intermittent pain (p<0.01), severe vision impairment (p<0.05), dysphagia for solids (p<0.01), and a generalized distribution of muscle atrophy (p<0.05). Female participants were significantly more likely to have contractures at birth (p<0.01), arthrogryposis multiplex congenita (p<0.001), spasticity on exam (p<0.1), and lower limb muscle atrophy (p<0.05). Of note, a phenotype characterized by less impairment in receptive language than expressive speech was common in both sexes (82% of participants of each sex for which language assessment was not limited due to age).

Our study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. This is helpful for clinicians when providing anticipatory guidance to the families of children with ZARD. Further analysis is needed to better understand the role that pathogenic variation type may play in phenotypic expression.