POLD3 deficiency is a very rare disorder. Originally described as an autosomal‐recessivecondition caused by biallelic loss-of-function or hypomorphic variants in POLD3, the gene encoding the POLD3 accessory subunit of DNA polymerase δ. It presents as a syndromic combined immunodeficiency (T-cell lymphopenia / SCID or Omenn-like phenotype) with variable neurodevelopmental delay and sensorineural hearing loss.
On cellular studies, POLD3 variants were shown to cause defective S-phase entry, replication stress, and accumulation of DNA damage, which likely underlie both immune and developmental phenotypes. Two reports of human cases with POLD3 deficiency have been described so far: one Lebanese family including four affected individuals presenting with severe combined immunodeficiency; and one boy with consanguineous parents of Moroccan descent, presenting as Omenn syndrome.
In addition, recently, autosomal-dominant, adult-onset, progressive sensorineural hearing loss and vestibular dysfunction (with possible early‐onset cancer predisposition) was linked to a heterozygous (monoallelic) POLD3 variant, thus expanding the phenotypic and inheritance spectrum of POLD3‐related disease.
Thus, prevalence is currently unknown but appears to be extremely rare. Inheritance patterns include:
• Autosomal recessive (biallelic variants) → severe immunodeficiency + multisystem involvement (neurological defects with or without congenital hearing loss).
• Autosomal dominant (monoallelic / haploinsufficiency) → primarily adult‐onset hearing/vestibular defects.
• Genetic counselling: depending on the variant and family context, both inheritance modes should be considered.
Diagnosis relies on genetic testing with additional testing depending on the context. Indeed, in case of biallelic mutations, genetic testing should be combined with immunological evaluation (immunophenotyping), neurological and hearing assessment, while in case of heterozygous variants, hearing and vestibular assessments are needed to complement genetic testing.
POLD3