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Familial medullary thyroid carcinoma (MTC) and its precursor, C-cell hyperplasia (CCH), are most often driven by germline RET mutations. However, in a RET-negative kindred, exome sequencing identified a novel ESR2 frameshift variant c.948del (p.Gly318AlafsTer22) that co-segregated with histologically confirmed CCH/MTC (PMID:26945007). This finding expands the genetic landscape of hereditary MTC/CCH to include ESR2.
Genetic evidence supports an autosomal dominant inheritance pattern. The ESR2 c.948del variant was detected in all affected relatives across a single multigenerational kindred, with loss of ERβ expression in tumour tissue. No additional unrelated probands have been reported to date, yielding limited genetic support under ClinGen criteria.
ESR2 encodes estrogen receptor β (ERβ), which forms heterodimers with ERα to repress estrogen-responsive element (ERE)-mediated transcription. The frameshift c.948del truncates ERβ, abrogating its repressor function on ERα, thereby permitting unopposed ERE activation.
In vitro assays in thyroid-derived cells showed that ERβ loss drives increased cellular proliferation, ERE reporter activation, and up-regulation of RET transcription. In vivo immunostaining of CCH and MTC specimens demonstrated markedly elevated RET expression in ESR2-mutant tissue compared to controls, consistent with the proposed mechanism.
No conflicting genetic or phenotypic data have been reported for ESR2 in MTC/CCH. Functional studies are concordant and mechanistically plausible, providing moderate experimental support.
Collectively, the evidence from a single family with segregation and robust functional data yields a Limited clinical validity classification. Identification of ESR2 loss-of-function variants can inform genetic testing for RET-negative familial MTC and guide surveillance strategies.
Gene–Disease AssociationLimitedSingle multigenerational family with a segregating ESR2 frameshift variant and no additional unrelated cases Genetic EvidenceLimitedOne heterozygous frameshift variant in a single kindred with segregation to disease Functional EvidenceModerateIn vitro and in vivo assays show ERβ loss leads to increased RET expression via unopposed ERα-driven ERE activation |