POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment

Cybel Mehawej (1) , Eliane Chouery (1) , Shirine Azar-Atallah (1) , Wassim Shebaby (1) , Valérie Delague (2) , Issam Mansour , Mirna Mustapha , Gerard Lefranc , Andre Megarbane (1)

1 LAU - Lebanese American University
2 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille

Combined immunodeficiency diseases (CID) represent the most severe forms of inborn errors of immunity. Defective T cell development and/or function, leading to an impairment in adaptive immunity are responsible for these diseases. The DNA polymerase δ complex is important for genome duplication and maintenance and consists of the catalytic subunit POLD1, and the accessory subunits POLD2 and POLD3 which stabilizes the complex. Mutations in POLD1 and POLD2 have been recently shown to be associated with a syndromic CID characterized by T cell lymphopenia with or without intellectual deficiency and sensorineural hearing loss. Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. The homozygous POLD3Ile10Thr variant abolishes POLD3 as well as POLD1 and POLD2 expression. Our findings implicate POLD3 deficiency as a novel cause of syndromic SCID.

Domaines: Génétique; Médecine humaine et pathologie

Cybel Mehawej, Eliane Chouery, Shirine Azar-Atallah, Wassim Shebaby, Valérie Delague, et al.. POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment. Clinical Immunology, 2023, 251, pp.109326. ⟨10.1016/j.clim.2023.109326⟩. ⟨hal-04113279⟩