Protocadherin alpha gene cluster variants are potentially associated with short root anomaly in Japanese.

Objectives: Short root anomaly (SRA) is a risk factor for root resorption, complicating orthodontic treatment. Familial occurrences of SRA suggest a genetic component in its pathogenesis; however, the specific gene responsible remains unidentified. This study aimed to identify the genes involved in the development of SRA using exome sequencing in Japanese individuals with SRA.

Methods: To identify the genes responsible for SRA in the Japanese population, we enrolled 433 patients and measured their root-to-crown (R/C) ratio of the maxillary central incisors using orthopantomograms to establish the phenotypic definition of SRA. Patients with teeth exhibiting R/C ratio measurements <-2 standard deviations (SD) were diagnosed as having an extreme SRA phenotype. Exome sequencing was conducted on 17 patients with extreme phenotypes, and the findings were validated through Sanger sequencing.

Results: The average R/C ratio of the maxillary central incisors <-2 SD was 0.87. We identified four missense variants in five cases within the protocadherin alpha (PCDHA) gene cluster, associated with calcium-dependent cell adhesion. The variants were as follows: PCDHA3 (c.79G>C, p.Gly27Arg), PCDHA6 (c.2279C>T, p.Ser760Phe), PCDHA9 (c.1490G>A, p.Arg497Gln), and PCDHA13 (c.1185C>A, p.Phe395Leu). Their pathogenicity was investigated via in silico analyses.

Limitations: Our study was a hospital-based study rather than a community-based one, and measurements of the maxillary central incisors were taken using orthopantomograms, which might have introduced bias.

Conclusions: Our findings suggest that the PCDHA gene cluster may be one of the genetic factors involved in the onset of SRA and that variants in this gene cluster could potentially affect tooth root development.