Genetic and clinical analysis of <i>OPTN</i> in amyotrophic lateral sclerosis.

Abstract

Considerable heterogeneity in genotypes and phenotypes has been observed among patients with amyotrophic lateral sclerosis (ALS) harbouring optineurin gene (<i>OPTN</i>) mutations, as reported in prior studies. The study aimed to elucidate the correlation between <i>OPTN</i> genotypes and phenotypes. <i>OPTN</i> gene variants were screened within a substantial Chinese cohort of patients with ALS, encompassing LoF and rare missense variants. Additionally, a systematic literature review was conducted to compile the spectrum of <i>OPTN</i> mutations and explore the relationship between the genotype and phenotype of patients with ALS with <i>OPTN</i>. A total of 33 unrelated patients with ALS with 24 rare <i>OPTN</i> variants, including 17 novel variants, were identified in 2279 patients with ALS. Among 24 variants in our cohort and 106 variants in previous studies, only 33.3% and 35.8% were pathogenic/likely pathogenic variants. Moreover, the frequency of <i>OPTN</i> variants in the Asian ALS population was higher (1.08%) than that of the Caucasian population (0.55%). For the phenotype of patients with ALS carrying OPTN variants, we found that patients with pathogenic/likely pathogenic variants had the highest baseline progression rate and the shortest survival time among groups in our cohort. Our study contributed to a broader understanding of the genotype and phenotype spectrum of patients with ALS carrying <i>OPTN</i> variants. Further investigations are warranted to definitively establish the genotype-phenotype associations.