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

Area of Science:

• Genetics
• Neuroscience
• Immunology

Background:

• Biallelic pathogenic variants in DIAPH1 are linked to a neurodevelopmental syndrome.
• This syndrome can present with varying degrees of immunodeficiency.

Purpose of the Study:

• To delineate the clinical and immunological characteristics of DIAPH1-related neuroimmunological syndrome.
• To investigate the role of DIAPH1 in development using vertebrate models.

Main Methods:

• Studied 53 individuals with biallelic DIAPH1 variants (33 new cases).
• Performed clinical analysis and functional studies in Danio rerio and Xenopus tropicalis knockout models.

Main Results:

• Identified key clinical features: developmental delay, intellectual disability, microcephaly, visual impairment, epilepsy, and brain abnormalities.
• Observed frequent respiratory infections, often linked to epilepsy and aspiration.
• Noted consistently low T-cell receptor excision circles (TRECs) and naive T-lymphocyte counts, despite normal lymphocyte subsets and immunoglobulins in most patients.
• Xenopus models showed growth and eye defects; zebrafish displayed seizure-like behavior.

Conclusions:

• DIAPH1 is essential for neurodevelopment, immune regulation, and DNA repair.
• DNA repair defects may increase susceptibility to infections, lymphoma, or treatment toxicity.
• Impaired T-cell maturation, indicated by low TRECs, suggests potential for early identification through newborn screening, preceding neurological symptom onset.