REST – Hereditary Gingival Fibromatosis

Hereditary gingival fibromatosis (HGF) is a rare, benign overgrowth of keratinized gingiva characterized by slow but progressive, non-hemorrhagic fibrous enlargement. HGF frequently follows an autosomal dominant inheritance pattern with high penetrance and variable expressivity, as illustrated by a single family in which a mother and three descendants exhibited phenotypes ranging from severe generalized gingival overgrowth in a 16-year-old proband to minimal manifestations in the mother (PMID:32413193). Histopathological examination supports the diagnosis, and clinical management often involves repeated gingivectomies or surveillance.

Genetic studies have identified truncating mutations in the final exon of REST in multiple unrelated families. A landmark report described 11 affected individuals across three families harboring frameshift and nonsense variants—c.2865_2866del (p.Asn958fs), c.2413del (p.Leu805fs), and c.1310T>A (p.Leu437Ter)—co-segregating with HGF (PMID:28686854). Subsequent whole-exome sequencing in 13 Brazilian patients from four families uncovered an additional REST frameshift variant, c.1493_1494del (p.Glu498GlyfsTer17), in two families, further reinforcing the association (PMID:35665929).

All five reported REST variants are predicted to truncate the protein within the last exon, clustering in the C-terminal domain. We highlight the representative variant c.1493_1494del (p.Glu498GlyfsTer17) identified in multiple families as illustrating the characteristic spectrum of REST lesions underlying HGF.

Functional assays in gingival fibroblasts and reporter systems demonstrate that these truncated REST isoforms display partial to complete loss of repressor activity. Co-expression of mutant and wild-type REST proteins impairs the repressive function of the full-length factor, consistent with a dominant-negative mechanism (PMID:33719663). Immunofluorescence confirms nuclear localization of truncated proteins, and immunohistochemistry reveals reduced REST reactivity in HGF gingiva compared to normal tissue.

Together, the segregation of truncating REST variants in at least five unrelated families (11 affected individuals in three families plus two further families), coupled with concordant functional data demonstrating dominant-negative disruption of REST-mediated silencing, provides strong clinical validity for REST in HGF. These findings reach the ClinGen criteria for a Strong gene–disease association.

Key Take-home: Heterozygous truncating mutations in the final exon of REST cause autosomal dominant HGF via a dominant-negative mechanism, supporting REST genetic testing and informing clinical surveillance and management.

References

• Special care in dentistry • 2020 • Nonsyndromic hereditary gingival fibromatosis: Characterization of a family and review of genetic etiology. PMID:32413193
• American journal of human genetics • 2017 • REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. PMID:28686854
• (unpublished) • 2022 • Hereditary gingival fibromatosis WES identifies novel REST variants. PMID:35665929
• Journal of dental research • 2021 • Novel REST Truncation Mutations Causing Hereditary Gingival Fibromatosis. PMID:33719663

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