New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes

• Published in: Journal of periodontology (1970) Vol. 94; no. 1; pp. 108 - 118
• Main Authors: Machado, Renato Assis, de Andrade, Rodrigo Soares, Pêgo, Sabina Pena Borges, Krepischi, Ana Cristina Victorino, Coletta, Ricardo D., Martelli‐Júnior, Hercílio
• Format: Journal Article
• Language: English
• Published: United States 01-01-2023
• Subjects: ALK; CD36; CD36 Antigens - genetics; Fibromatosis, Gingival - genetics; Fibromatosis, Gingival - pathology; Genetic Heterogeneity; gingival fibromatosis; Humans; Pedigree; Receptor Protein-Tyrosine Kinases - genetics; REST; SOS1; ALK; REST; CD36; SOS1; gingival fibromatosis
• ISSN: 0022-3492; 1943-3670
• DOI: 10.1002/JPER.22-0219

Background
Hereditary gingival fibromatosis (HGF) is an uncommon genetic condition characterized by slow but progressive fibrous, non‐hemorrhagic, and painless growth of the gingival tissues due to the increased deposition of collagen and other macromolecules of the extracellular matrix. HGF occurs in approximately 1:750,000 individuals and can exhibit dominant or recessive inheritance. To date, five loci (2p21‐p22, 2p22.3‐p23.3, 4q12, 5q13‐q22, and 11p15) and three genes [REST (RE1‐silencing transcription factor), SOS1 (Son‐of‐Sevenless‐1), and ZNF862 (zinc finger protein 862 gene)] have been associated with HGF. Here, our study aimed to identify genetic variants associated with HGF by applying whole‐exome sequencing (WES) and bioinformatics analyses.
Methods
Thirteen Brazilian individuals with HGF and nine relatives without HGF from four unrelated families were chosen for our investigation. Blood collected from the patients and their relatives were used for WES. Five Web‐available tools, namely, CADD, PolyPhen, SIFT, Mutation Taster, and Franklin's algorithms, were used to predict protein damage.
Results
WES revealed pathogenic variants affecting the known HGF genes REST (c.1491_1492delAG) and SOS1 (c.3265_3266insTAAC) in two families. Additionally, potentially pathogenic variants segregating in the other two families were mapped to ALK receptor tyrosine kinase gene (ALK) (c.361C > T) and to collagen type I receptor and thrombospondin receptor gene (CD36) (c.1133G > T).
Conclusion
Our findings reinforce the high genetic heterogeneity of HGF, identifying new variants in HGF known genes (REST and SOS1) and ALK and CD36 as new genes that cause HGF.