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XB-ART-61773
Genet Med 2026 Mar 17;285:102551. doi: 10.1016/j.gim.2026.102551.
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Recessive loss of DIAPH1 function causes a progressive neurodevelopmental syndrome with variable immunological involvement.

Galassi Deforie V, Maroofian R, Karagoz I, Godwin A, Al Sheikh E, Gestri G, Zaki MS, Woodward BL, Ghorab RM, Alvi JR, Alabdi L, Damseh N, Elshafie RM, Scardamaglia A, Alves C, Shaikh M, Özcan GG, Sadek AA, Issa MY, Striano P, Suri M, Murphy D, Ashhab M, de la Fuente RP, Arteche-López A, Hashem MO, Abdulwahab F, Aboelanine AH, Alkhawaja IA, Ibrahim S, van der Burg M, Berghuis D, Santen GW, Toosi MB, Alerasool M, Eslahi A, Srinivasan VM, Gowda VK, Trollmann R, Vasileiou G, Pauly M, Hashemi-Gorji F, Miryounesi M, Salpietro V, Al-Herz W, Carter SP, Briggs TA, Hussell T, Ruuska-Loewald T, Komulainen-Ebrahim J, Uusimaa J, Hautala T, Potluri S, Shackley F, Mojarrad M, Chung WK, Wilson SW, Sultan T, Gleeson JG, Marafi D, Alkuraya FS, Stewart GS, Efthymiou S, Guille M, Arkwright PD, Houlden H.


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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: A total of 53 individuals with biallelic DIAPH1 variants, including 33 previously unreported patients, were studied. Clinical features were analyzed, 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, whereas zebrafish exhibited no overt malformations but showed seizure-like behavior in Phenothiazine assays. CONCLUSION: 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 that these patients could be identified by T cell excision circles newborn screening before neurological symptoms develop.

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???displayArticle.link??? Genet Med


Species referenced: Xenopus tropicalis
Genes referenced: diaph1
GO keywords: regulation of immune system process [+]

???displayArticle.disOnts??? microcephaly
???displayArticle.omims??? DEAFNESS, AUTOSOMAL DOMINANT 1, WITH OR WITHOUT THROMBOCYTOPENIA; DFNA1 [+]