Exome Sequencing of 5 Families with Severe Early-Onset Periodontitis

Abstract

Periodontitis is characterized by alveolar bone loss leading to tooth loss. A small proportion of patients develop severe periodontitis at the juvenile or adolescent age without exposure to the main risk factors of the disease. It is considered that these cases carry rare variants with large causal effects, but the specific variants are largely unknown. In this study, we performed exome sequencing of 5 families with children who developed stage IV, grade C, periodontitis between 3 and 18 y of age. In 1 family, we found compound heterozygous variants in the gene CTSC (p.R272H, p.G139R), 1 of which was previously identified in a family with prepubertal periodontitis. Subsequent targeted resequencing of the CTSC gene in 24 patients <25 y of age (stage IV, grade C) identified the known mutation p.I453V (odds ratio = 4.06, 95% CI = 1.6 to 10.3, P = 0.001), which was previously reported to increase the risk for adolescent periodontitis. An affected sibling of another family carried a homozygous deleterious mutation in the gene TUT7 (p.R560Q, CADD score >30 [Combined Annotation Dependent Depletion]), which is implicated in regulation of interleukin 6 expression. Two other affected siblings shared heterozygous deleterious mutations in the interacting genes PADI1 and FLG (both CADD = 36), which contribute to the integrity of the environment–tissue barrier interface. Additionally, we found predicted deleterious mutations in the periodontitis risk genes ABCA1, GLT6D1, and SIGLEC5. We conclude that the CTSC variants p.R272H and p.I453V have different expressivity and diagnostic relevance for prepubertal and adolescent periodontitis, respectively. We propose additional causal variants for early-onset periodontitis, which also locate within genes that carry known susceptibility variants for common forms. However, the genetic architecture of juvenile periodontitis is complex and differs among the affected siblings of the sequenced families.

A genome‐wide association study meta‐analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci

“…Notably, in a study aimed at identifying causative mutations for severe adolescent‐onset periodontitis, a highly deleterious missense mutation (rs1404827864, CADD = 29, gnomAD genomes European MAF = 0.00003) within HMCN1 was detected by whole exome sequencing. This mutation was found in two affected children with stage III/IV‐C periodontitis that was diagnosed at adolescent age (Richter et al, 2022), but not in a healthy sibling. Taken together, it is conceivable that HMCN2 is an important factor in human tissue (re‐)modelling and may play a role in periodontal tissue repair and wound healing.…”

“…rs11084095 was also among the associated variants in the present meta‐GWAS. Furthermore, within SIGLEC5 , a deleterious rare frameshift mutation (rs149243374, CADD = 24.0, ExAc EUR MAF = 0.00455) was found by whole exome sequencing in a family of adolescent stage III, grade C periodontitis (Richter et al, 2022).…”

miRNAs from Inflamed Gingiva Link Gene Signaling to Increased MET Expression

“…We found that 3 miRNAs each regulated a periodontitis risk gene. These were CPEB1 ( Rhodin et al 2014 ), ABCA1 ( Richter et al 2022 ), and ATP6V1C1 ( Munz et al 2019 ), which were regulated by hsa-miR-130a-3p, hsa-miR-144-3p, and hsa-miR-144-5p, respectively. In addition, CPEB1 and ATP6V1C1 were among the 10 most downregulated genes after miRNA upregulation.…”

Epigenetics in susceptibility, progression, and diagnosis of periodontitis

“…So far, functional alteration of NOD2 caused by each mutation has not been revealed. Most recently, exosome sequencing of children who developed stage IV, grade C periodontitis identified mutations in gene loci of CTSC , TUT7 , PADI1 , FLG , ABCA1 , GLT6D1 , and SIGLEC5 [28] . Thus, the genetic background responsible for AP has mostly been clarified.…”