Gene/function:
POLD3encodes the accessory subunit of DNA polymerase δ (Pol δ), important for DNA replication, replication‐associated repair and genomic stability.
Type of variants and inheritance:
• Recessive form: Biallelic loss‐of‐function or severely hypomorphic POLD3 variants (autosomal recessive). To date, two variants have been reported in the recessive form in POLD3 (NM_006591.3): c.29T>C; p.Ile10Thr, and c.1118A > C; p.K373T.
• Dominant form: POLD3 variant (haploinsufficiency) was associated with adult‐onset hearing and vestibular impairment.
Mechanism (suspected):
Functional data in the patient with Omenn syndrome show defective S‐phase entry, replication stress, and increased DNA damage foci.
• In the recessive form: Severe impairment of Pol δ accessory subunit leading to major replication stress.
• In the dominant form: Haploinsufficiency of POLD3 leads to milder but cumulative replication/repair defect, associated with late‐onset cochlear/vestibular cell vulnerability.
• Diagnostic testing: Genetic sequencing (WES or gene panel), Sanger confirmation, segregation; immunologic/functional assays for recessive cases; for dominant cases, audiologic/vestibular testing in carriers plus possible cancer surveillance.
POLD3