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 (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 28

Article Number: 102551

Journal Issue: 5

DOI: 10.1016/j.gim.2026.102551

Abstract

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.

Authors with CRIS profile

Involved external institutions

University of Portsmouth United Kingdom (GB) University of Manchester United Kingdom (GB) University College London (UCL) United Kingdom (GB) Istituto Giannina Gaslini Italy (IT) Nottingham University Hospitals United Kingdom (GB) Indira Gandhi Institute of Child Health India (IN) Sheffield Children's NHS Foundation Trust United Kingdom (GB) National Research Centre (NRC) / المركز القومي للبحوث Egypt (EG) Mashhad University of Medical Sciences (MUMS) Iran, Islamic Republic of (IR) University of Birmingham United Kingdom (GB) Boston Children's Hospital United States (USA) (US) University of Child Health Sciences Pakistan (PK) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) King Faisal Specialist Hospital & Research Centre Saudi Arabia (SA) Ministry of Health Kuwait (KW) Al-Quds University / جامعة القدس‎‎ Israel (IL) Harvard University United States (USA) (US) Sohag-University Egypt (EG) Hospital Universitario 12 de Octubre Spain (ES) AlBashir Hospital Jordan (JO) Aga Khan University (AKU) / آغا خان یونیورسٹی‎ Pakistan (PK) Leiden University Medical Center Netherlands (NL) Shahid Beheshti University of Medical Sciences Iran, Islamic Republic of (IR) University of L'Aquila / Università degli Studi dell'Aquila Italy (IT) Kuwait University Kuwait (KW) Oulun Yliopisto / University of Oulo Finland (FI)

How to cite

APA:

Galassi Deforie, V., Maroofian, R., Karagoz, I., Godwin, A., Al Sheikh, E., Gestri, G.,... Houlden, H. (2026). Recessive loss of DIAPH1 function causes a progressive neurodevelopmental syndrome with variable immunological involvement. Genetics in Medicine, 28(5). https://doi.org/10.1016/j.gim.2026.102551

MLA:

Galassi Deforie, Valentina, et al. "Recessive loss of DIAPH1 function causes a progressive neurodevelopmental syndrome with variable immunological involvement." Genetics in Medicine 28.5 (2026).

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