POLE – IMAGE-I syndrome

DNA polymerase epsilon catalytic subunit 1 (POLE) is a core component of the eukaryotic DNA replisome responsible for leading‐strand synthesis and proofreading. Biallelic POLE mutations underlie IMAGE-I syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency) through impaired DNA replication and cell cycle control. The autosomal recessive inheritance is supported by compound heterozygous and homozygous variants in affected individuals.

Two unrelated patients with IMAGE-I syndrome were reported, each harboring biallelic POLE variants: a shared deep intronic mutation (c.1226+234G>A) causing aberrant splicing, and patient-specific coding changes (missense c.2593T>G (p.Trp865Gly) and in-frame deletion c.711_713del) (PMID:35534205). No additional segregation beyond the two probands has been described, consistent with autosomal recessive transmission.

The variant spectrum comprises one deep intronic splice-altering allele and two hypomorphic coding alleles: a missense substitution, c.2593T>G (p.Trp865Gly), and an in-frame deletion, c.711_713del. All variants are novel and absent from population databases. The inheritance mode is autosomal recessive with compound heterozygosity and homozygosity observed in non‐consanguineous families.

Functional studies in patient fibroblasts and transfected cell lines demonstrated significantly reduced POLE mRNA and protein levels, severely diminished nuclear localisation rescued by proteasome inhibition, impaired S-phase progression, and elevated phospho-H2AX signaling, indicating replication stress and DNA damage (PMID:35534205). These concordant experimental findings support a loss-of-function mechanism via proteasome-dependent degradation in the nucleus.

No conflicting reports have been published. Integration of genetic and functional data yields a ClinGen clinical validity classification of Moderate, reflecting two unrelated probands with biallelic variants and robust mechanistic evidence. Further independent case reports and segregation data would strengthen the association towards Strong or Definitive.

Key Take-home: Biallelic POLE variants cause IMAGE-I syndrome by triggering proteasome-dependent POLE degradation, leading to replication stress and multisystem developmental defects, informing molecular diagnosis and genetic counseling.

References

• Journal of medical genetics • 2022 • Novel POLE mutations identified in patients with IMAGE-I syndrome cause aberrant subcellular localisation and protein degradation in the nucleus. PMID:35534205

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