Detecting Rare Variants in PCDHGB1 in Dystonia.
BACKGROUND Recently, PCDHGB1 has been identified as a novel causative gene of dystonia predominantly affecting the cervical muscles. However, no large cohort study has been conducted to confirm the association. OBJECTIVES The objective of the study was to systematically evaluate the genetic associations of PCDHGB1 with dystonia in a large Chinese dystonia cohort. METHODS We analyzed rare variants of PCDHGB1 in a discovery cohort, including 878 dystonia patients, and a validation cohort, including 509 dystonia patients, using whole-exome sequencing. The overrepresentation of rare variants in patients was examined using Fisher's exact test at allele and gene levels. RESULTS Twenty-seven rare variants of PCDHGB1 were identified in 55 individuals in the discovery cohort, including 3 frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51) and 24 missense variants. Another 10 rare variants were detected in 12 patients in the validation cohort, including 1 frameshift variant (p.Leu709Argfs*13) and 9 missense variants. Fourteen patients carried the frameshift variant p.Leu177Valfs*7. Thirteen patients carried the p.Met111Val variant, including 3 patients from one family. At variant level, p.Pro773Ser and p.Arg408Gln were significantly associated with a higher risk of dystonia, whereas 15 variants (including p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13, and 12 missense variants) were nominally associated with a higher risk of dystonia. Gene-based burden analysis detected the enrichment of ultra-rare variants of PCDHGB1 in dystonia. Western blot experiments revealed that these four frameshift variants (p.Leu177Valfs*7, p.Arg635Profs*24, p.Asp797Glufs*51, p.Leu709Argfs*13) induced a truncated PCDHGB1 protein. CONCLUSIONS Our study supplemented the evidence on the role of PCDHGB1 in dystonia and expanded the genotypic and phenotypic spectrum of PCDHGB1. © 2026 International Parkinson and Movement Disorder Society.