Exploring the phenotypic fingerprints of ANXA11 variants in ALS: a population-based study in an European cohort

Background: Annexin A11 (ANXA11) has emerged as a significant gene associated with amyotrophic lateral sclerosis (ALS) and cognitive impairments. This study aimed to evaluate the prevalence and clinical and cognitive features of pathogenic variants in ANXA11 in an Italian ALS cohort. Methods: Data were collected from the Piemonte and Valle d’Aosta Register for ALS between 2009 and 2020. Only patients who underwent whole genome sequencing (WGS) were included. Clinical and cognitive assessments were compared among patients with ANXA11-ALS, wild-type ALS (WT-ALS), and C9ORF72-ALS. Results: Among 1,486 ALS patients, 18 (1.4%) were found to carry ANXA11 variants, four of which were classified as benign or likely benign. Three patients (16.7%) also had co-occurring variants in ERBB4 (erb-b2 receptor tyrosine kinase 4), EPHA4 (ephrin type-A receptor 4), or C9ORF72 (chromosome 9 open reading frame 72). Patients with ANXA11-ALS had significantly lower education levels (6.2 vs. 8.9 years), higher BMI at diagnosis (26.7 vs. 24.5), and a higher prevalence of cognitive impairment (100% vs. 47%) compared to WT-ALS. Cognitive testing revealed more severe deficits in executive function, attention, psychomotor speed, non-verbal intelligence, and cognitive flexibility, though no behavioral differences were observed. Compared to C9ORF72-ALS, ANXA11-ALS patients were older at diagnosis (66.6 vs. 60.3 years), had lower education levels (6.2 vs. 9.0 years), and higher rates of cognitive impairment (100% vs. 68.7%). Discussion: Pathogenic ANXA11 variants are relatively common in ALS and are strongly associated with cognitive impairment. Including ANXA11 in routine genetic screening may enhance diagnostic precision and therapeutic strategies for ALS patients.