Detecting Rare Variants in PCDHGB1 in Dystonia.

Rare PCDHGB1 variants enriched in dystonia patients; four frameshift variants produce a truncated PCDHGB1 protein on western blot.

PCDHGB1 was recently proposed as a causative gene for dystonia predominantly affecting cervical muscles, without confirmation in a large cohort. The authors analysed rare PCDHGB1 variants by whole-exome sequencing in a Chinese discovery cohort of 878 dystonia patients and a validation cohort of 509 patients. Twenty-seven rare variants were identified in 55 individuals in the discovery cohort (3 frameshift, 24 missense) and ten further variants in 12 patients in the validation cohort. At variant level, p.Pro773Ser and p.Arg408Gln were significantly associated with increased dystonia risk, and gene-based burden analysis showed enrichment of ultra-rare variants; western blot confirmed that the four frameshift variants produce a truncated protein.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Replication in two independent cohorts, with burden analysis and functional validation of the frameshift variants, substantially strengthens the PCDHGB1–dystonia link that the initial description lacked. Note the level of evidence, however: these are cohort-level risk associations, not variant-by-variant Mendelian causality — nominally associated missense variants cannot be reported as pathogenic in an individual diagnosis. The cohort is entirely Chinese, which limits direct transfer of allele frequencies to other populations.

Analysis by Dr Thibaut Benquey