Detecting Rare Variants in PCDHGB1 in Dystonia

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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.

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