Mutation screening of AOPEP variants in a large dystonia cohort

Study objectives Recently, AOPEP has been identified to be a novel causative gene of autosomal-recessive dystonia. However, no large cohort study has been conducted to confirm the association. We aimed to systematically evaluate the genetic associations of AOPEP with dystonia in a large Chinese dystonia cohort. Methods We analyzed rare variants of AOPEP in 878 dystonia patients with whole-exome sequencing. The over-representation of rare variants in patients was examined with Fisher’s exact test at allele and gene levels. Results Among the 878 patients with dystonia, we found two patients with biallelic likely pathogenic variants in the AOPEP gene. One patient carried putative compound heterozygous variants (p.A212D and p.G216R) and presented with childhood-onset segmental dystonia involving the upper limbs and craniocervical muscles accompanied by myoclonus of the dystonia affected areas. One patient carried homozygote of p.M291Nfs*68 and presented with adult-onset isolated cervical dystonia. Another 15 patients were identified to carry heterozygous rare variants in AOPEP , including 2 loss-of-function variants (p.M291Nfs*68 and p.R493X) and 6 missense variants. One loss-of-function variant (p.R493X) was the same as previously reported. Nearly, all of the 15 patients carrying heterozygous variants in AOPEP presented with isolated dystonia with only craniocervical muscles affected, except for one patient who carried the p.R493X variant presented with segmental dystonia affecting the neck and right upper limb combined with parkinsonism. Gene-based burden analysis detected enrichment of rare variants and rare damaging variants of AOPEP in dystonia . Conclusions Our study supplemented the evidence on the role of AOPEP in autosomal-recessive dystonia in Chinese population, and expanded the genotypic and phenotypic spectrum of AOPEP.