IADR Abstract Archives
Exome-Sequencing of 5 Families With Severe Early-Onset Periodontitis
Objectives: Periodontitis (PD) is characterized by alveolar bone loss leading to tooth loss. A small proportion of cases develop severe PD at juvenile or adolescent age without exposure to the main disease risk factors. It is considered that these cases carry mutations with large causal effects but they are largely unknown. To identify such mutations, we performed whole exome sequencing (WES) and targeted resequencing with 5 families with children that developed stage IV grade C PD between 3 and 18 years.
Methods: 5 families were selected for WES with stage III or IV, grade C PD diagnosed in their underaged siblings. The gene Cathepsin C (CTSC) was sequenced in 24 additional cases with PD stage IV grade C at ≥ 3 teeth with ≤ 25 years of age. We filtered mutations with a frequency < 0.002 and a Combined Annotation Dependent Depletion score (CADD) ≥ 20 from the WES data.
Results: In one family, we found compound heterozygous variants in the gene CTSC (p.R272H, p.G139R), one of which was previously identified in a family with prepubertal PD. Resequencing of CTSC in 24 cases (stage IV grade C) under 25 years of age identified the known mutation p.I453V (odds ratio = 4.06 (95% confidence interval = 1.6-10.3); P = 0.001) previously found in adolescent PD patients. A sibling of another family carried a homozygous mutation in TUT7 (p.R560Q, CADD > 30), which is implicated in regulation of IL6 gene expression. Two other siblings shared heterozygous mutations in the interacting genes PADI1 and FLG (CADD = 36), which contribute to barrier integrity. We also found deleterious mutations in the PD risk genes ABCA1, GLT6D1, and SIGLEC5.
Conclusions: We conclude that the CTSC variants p.R272H and p.I453V have different expressivity and are of diagnostic relevance for prepubertal and adolescent PD, respectively. Additional putative causal mutations for early-onset PD located within genes that carry known susceptibility variants for common forms. The genetic architecture of juvenile PD is complex and differs between the affected siblings of the sequenced families.
Methods: 5 families were selected for WES with stage III or IV, grade C PD diagnosed in their underaged siblings. The gene Cathepsin C (CTSC) was sequenced in 24 additional cases with PD stage IV grade C at ≥ 3 teeth with ≤ 25 years of age. We filtered mutations with a frequency < 0.002 and a Combined Annotation Dependent Depletion score (CADD) ≥ 20 from the WES data.
Results: In one family, we found compound heterozygous variants in the gene CTSC (p.R272H, p.G139R), one of which was previously identified in a family with prepubertal PD. Resequencing of CTSC in 24 cases (stage IV grade C) under 25 years of age identified the known mutation p.I453V (odds ratio = 4.06 (95% confidence interval = 1.6-10.3); P = 0.001) previously found in adolescent PD patients. A sibling of another family carried a homozygous mutation in TUT7 (p.R560Q, CADD > 30), which is implicated in regulation of IL6 gene expression. Two other siblings shared heterozygous mutations in the interacting genes PADI1 and FLG (CADD = 36), which contribute to barrier integrity. We also found deleterious mutations in the PD risk genes ABCA1, GLT6D1, and SIGLEC5.
Conclusions: We conclude that the CTSC variants p.R272H and p.I453V have different expressivity and are of diagnostic relevance for prepubertal and adolescent PD, respectively. Additional putative causal mutations for early-onset PD located within genes that carry known susceptibility variants for common forms. The genetic architecture of juvenile PD is complex and differs between the affected siblings of the sequenced families.