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Polymerase epsilon catalytic subunit (POLE) is critical for leading-strand DNA synthesis and replication fidelity. Biallelic deficiency of POLE has been implicated in a multisystem developmental disorder resembling IMAGe syndrome. IMAGe syndrome is characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and variable immunodeficiency.
In a cohort of 15 affected individuals from 12 unrelated families with autosomal recessive inheritance, all carried a shared intronic splice-site variant, c.1686+3>G, on one allele and diverse loss-of-function variants on the other (PMID:30503519). This intronic change alters normal splicing, and together with trans LoF alleles, results in Pol ε haploinsufficiency (PMID:30503519).
Affected individuals uniformly presented with severe intrauterine growth restriction, metaphyseal dysplasia (HP:0100255), adrenal hypoplasia congenita (HP:0008244), and, in males, genitourinary anomalies. Additional features included distinctive facial dysmorphism and lymphocyte deficiency leading to recurrent infections.
Functional assays demonstrated that c.1686+3>G disrupts exon 14 splice donor usage, producing aberrant transcripts with premature termination. Patient cells exhibit markedly reduced POLE1 protein levels, delayed S-phase progression, and replicative stress consistent with a replisome defect (PMID:30503519).
No studies have reported conflicting genotype–phenotype correlations or alternative diagnoses in these families. The concordance of clinical, genetic, and cellular data supports a causal role for POLE deficiency in IMAGe syndrome.
In summary, biallelic POLE variants cause an autosomal recessive IMAGe syndrome via a hypomorphic mechanism leading to Pol ε insufficiency. Clinical screening of POLE should be considered in patients with growth restriction, metaphyseal dysplasia, adrenal insufficiency, and immunodeficiency. Key take-home: POLE loss-of-function is a confirmed genetic etiology of IMAGe syndrome and informs genetic diagnosis and management.
Gene–Disease AssociationStrong15 probands from 12 unrelated families with consistent AR inheritance and concordant cellular phenotype (PMID:30503519) Genetic EvidenceStrong15 probands, biallelic variants including recurrent intronic splicing variant in trans with LoF alleles; autosomal recessive inheritance (PMID:30503519) Functional EvidenceModerateSplicing assays and cellular studies show aberrant transcript, reduced Pol ε protein, delayed S-phase progression consistent with disease mechanism (PMID:30503519) |