Preprint: biological sex shapes disease severity and drug response in a mouse model of Helsmoortel-Van der Aa syndrome

Helsmoortel-Van der Aa syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in ADNP, a gene encoding a chromatin-remodelling protein. The condition is characterised by intellectual disability, autism spectrum features, and substantial clinical heterogeneity. A preprint posted to bioRxiv investigates whether biological sex modifies disease biology and treatment response in this syndrome.

The researchers studied male and female mice heterozygous for an Adnp frameshift variant (p.Leu822Hisfs*6) and examined behavioural and molecular outcomes, as well as response to davunetide (NAP), an investigational neuroprotective peptide. The preprint reports that sex influenced the consequences of Adnp deficiency at both behavioural and molecular levels, and affected the response to davunetide treatment. Clinical phenotyping data from individuals with Helsmoortel-Van der Aa syndrome were also examined for sex-related differences.

The study contributes to a growing body of work examining sex as a biological variable in neurodevelopmental disorders — an area of increasing importance given that conditions such as autism spectrum disorder show well-documented sex differences in presentation. The preprint has not yet been peer reviewed.

This finding is of primary interest to researchers in neurodevelopmental genetics, preclinical therapeutic modelling, and the basic biology of ADNP-associated disorders, and to educators covering sex differences in genetics and neurodevelopment.