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FILS syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the POLE gene. To date, only a single homozygous missense c.100C>T (p.Arg34Cys) variant has been reported in a child presenting with classical features of facial dysmorphism, immunodeficiency, livedo, short stature, and poikiloderma (PMID:32705701). No additional unrelated probands or segregation data have been described, and no functional studies have yet substantiated the pathogenic effect of this variant on polymerase ε activity. The variant affects the proofreading domain of POLE and is predicted to impair DNA replication fidelity, consistent with multisystemic manifestations. In the absence of replication or rescue models, mechanistic understanding remains inferential. Further cases and functional validation will be necessary to confirm causality. Key take-home: biallelic POLE c.100C>T (p.Arg34Cys) should be considered in the diagnostic evaluation of FILS syndrome.
Gene–Disease AssociationLimitedSingle homozygous proband with characteristic phenotype and no segregation or functional concordance (PMID:32705701) Genetic EvidenceLimitedOne autosomal recessive case with a homozygous missense variant in POLE; no additional segregation data Functional EvidenceNoneNo experimental studies available linking the POLE variant to FILS syndrome |