Lena Guillot-Noel

Background: Association between monoallelic STUB1 variant and expanded ATXN8OS alleles was recently reported, suggesting a pathogenic interaction that may influence spinocerebellar ataxia type 48 (SCA48) phenotype. Objectives: We investigated the frequency and clinical impact of ATXN8OS in a large cohort of STUB1 carriers compared to individuals with other ataxias and controls. Methods: Ataxic individuals and controls from the SPATAX/BIOMOV cohorts (Paris Brain Institute) were screened for ATXN8OS and other CAG expansions using polymerase chain reaction (PCR)/repeat‐prime PCR (RP‐PCR) and ExpansionHunter . STUB1 carriers underwent whole‐genome or exome sequencing. Results: Our cohort comprised 12 biallelic STUB1 carriers (SCAR16) and 67 monoallelic STUB1 carriers (SCA48) without other causative variants. ATXN8OS expansions (84–177 CTA/CTG repeats) were identified in seven SCA48 individuals (10.5%) who exhibited earlier onset (median age 28 vs. 47 years, P < 0.001) compared to other SCA48 individuals but with similar clinical presentation. ATXN8OS expansions were also found in two healthy controls older than 50 years (2/286, 0.7%) and in eight index cases with autosomal dominant ataxia (8/400, 2%), including four carrying another molecular diagnosis without any effect on the phenotype. Other intermediate expansions were identified in individuals with SCA48: seven (10.5%) carried intermediate TBP alleles (40–46 CAG/CAA) without any effect on dementia prevalence; four carried intermediate HTT alleles (28–29 CAG); and three carried intermediate ATXN1 expansions (38 CAG). Conclusions: ATXN8OS intermediate expansion acts as a genetic modifier in SCA48 but not in other ataxias. Moreover, expanded intermediate alleles in neurodegenerative disease genes were present in one‐third of SCA48 individuals. These alleles may increase polyglutamine burden, potentially saturating STUB1 E3 ubiquitin ligase activity. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background/Objectives: Autophagy is a highly conserved eukaryotic cellular process whose dysfunction results in human pathologies including cancer and neurodegenerative disease. First identified in yeast, ATG genes are central players in autophagy. Mutations in core autophagy genes ATG5 and ATG7 have been previously reported to cause rare genetic disorders with autosomal recessive inheritance. Methods: Here we report, for the first time, variants in human ATG9B gene as causative factors for a rare neurodevelopmental disease with autosomal recessive inheritance. Three distinct mutations were detected in three independent families with consanguinity, five patients affected in total. Results: The first variant is an 11-nucleotide deletion resulting in a frameshift. A premature stop codon is added and the C-terminal cytosolic domain of ATG9B protein is truncated. The second one is a point mutation that changes a critical amino acid in the transmembrane domain. The third variant is a 2-nucleotide deletion causing a different truncation product. Patients presented with diverse neurodevelopmental anomalies including intellectual disability, behavioral abnormalities, congenital cerebellar ataxia, mild cerebellar atrophy, and microcephaly. Since human ATG9B is expressed specifically in the placenta, we hypothesized that the disease pathology originates during placental development. To characterize the effects of the first frameshift mutation and gain insight into the specific functions of ATG9B in a physiological setting, we used mammalian cells and a knock-in mouse model. Truncated ATG9B was not stable when expressed in cells. It was localized to perinuclear vesicles like the WT protein, but not to peripheral vesicles. Homozygous knock-in mice were viable, fertile, and displayed no gross phenotypical abnormalities. Histomorphometry analysis of the placenta layers did not reveal a significant difference between mutant and control embryos. The assessments of neurobehavioral tests were similar in wild-type and homozygous knock-in mice. However, knock-in mice had a reduced fear memory trend, which is an amygdala-involved response. Conclusions: In this study, we describe a new rare disease linked to ATG9, including cerebellar ataxia and atrophy, as described for ATG5 and ATG7.

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.