Recessive loss of DIAPH1 function causes a progressive neurodevelopmental syndrome with variable immunological involvement

Purpose: Biallelic DIAPH1 pathogenic variants cause a neurodevelopmental syndrome occasionally associated with immunodeficiency. This study aims to define the clinical and immunological spectrum of DIAPH1-related neuroimmunological syndrome and explore the gene’s developmental role using vertebrate models.

Methods: 53 individuals with biallelic DIAPH1 variants, including 33 previously unreported patients were studied. Clinical features were analysed and functional studies were conducted using knockout models in Danio rerio and Xenopus tropicalis.

Results: Clinical features included developmental delay, intellectual disability, progressive microcephaly, cortical visual impairment or blindness, epilepsy, and frequent occipital-predominant brain abnormalities. Almost half suffered from infections, mainly affecting their respiratory tract related to epilepsy and aspiration. Although the majority had normal lymphocyte subsets and serum immunoglobulins, T-cell receptor excision circles and naïve T-lymphocyte counts were consistently low. The Xenopus model mirrored growth and eye defects seen in humans, while zebrafish exhibited no overt malformations but showed seizure-like behaviour in Phenothiazine assays.

Conclusions: DIAPH1 is critical for neurodevelopment, immune regulation, and DNA repair. The DNA repair defect may influence susceptibility to infection, lymphoma, or treatment-related toxicity. Although absolute T-cell numbers are not consistent with SCID, impaired T-cell maturation suggests these patients could be identified by TREC newborn screening before neurological symptoms develop.