Background and Objectives Bilateral vestibulopathy (BVP) is a chronic disorder resulting from bilateral loss of peripheral vestibular function. Although several etiologies have been identified, such as ototoxic exposure, bilateral Meni & egrave;re disease, and, more recently, monogenic causes including RFC1-related disorders and FGF14-GAA ataxia (SCA27B), a substantial proportion of cases remain idiopathic.Methods We performed a genome-wide association study (GWAS) in a European cohort of 132 individuals with idiopathic BVP and 3,410 unaffected controls. Clinical and demographic data were collected from affected individuals. Patients were diagnosed according to the B & aacute;r & aacute;ny Society criteria using video head-impulse testing and/or caloric irrigation. After stringent quality control and outlier removal, genome-wide association testing was conducted on approximately 7.3 million imputed variants, followed by gene-based and functional post-GWAS analyses, including functional variant annotation, expression quantitative trait locus (eQTL) mapping, chromatin interaction analysis, gene-set enrichment, and regulatory motif annotation.Results Three variants at 2 loci reached genome-wide significance. The strongest association was observed at the chromosome 19p12 ZNF91/LINC01224 locus, comprising rs12185481 located upstream of LINC01224 (p = 3.60E-16) and rs8108073 located within intron 3 of ZNF91 (p = 8.76E-12). A second signal was detected on chromosome 2q37.3 (rs73006457, p = 4.46E-08), located in a gene-poor region, with GPC1 and OTOS as the nearest protein-coding genes, both situated more than 100 kb away. Gene-based analysis identified ZNF91 as significantly associated. Functional annotation prioritized key candidate genes and indicated regulatory effects at the chromosome 19p12 locus, including eQTL signals across brain regions-most prominently in the cerebellum-as well as enrichment of gene sets related to transcriptional regulation, and predicted alterations of transcription factor binding motifs.Discussion This study identifies the ZNF91/LINC01224 locus on chromosome 19p12 as a major genetic risk factor for idiopathic BVP, pointing to a cis-regulatory mechanism within a single topologically associating domain, with downstream effects on ZNF91 expression. The secondary locus on chromosome 2q37.3 represents a less robust signal. These findings warrant replication in larger, independent cohorts.
Background and Objectives Non-5q spinal muscular atrophy (SMA) is genetically heterogeneous, yet many adult-onset cases remain molecularly undiagnosed. CGG repeat expansions in the 5 ' untranslated region of LRP12, originally identified in oculopharyngodistal myopathy, have also been implicated in amyotrophic lateral sclerosis (ALS) and inherited peripheral neuropathy. The aim of this study was to determine whether LRP12 CGG repeat expansions occur in patients with adult-onset proximal-predominant non-5q SMA and characterize the associated clinical presentations.Methods In this observational case series, we enrolled 8 consecutive, genetically unresolved families that met prespecified criteria for adult-onset non-5q SMA after exclusion of known genetic causes of SMA and familial ALS by comprehensive genetic evaluation, including whole-exome sequencing. LRP12 CGG repeat expansions were screened by repeat-primed PCR and then confirmed and sized by Oxford Nanopore long-read sequencing. LRP12 CGG repeat expansions were also screened in 496 unrelated ALS cases and 1,000 controls.Results Monoallelic LRP12 CGG repeat expansions were identified in 6 of the 8 non-5q SMA probands (75%). Five of the 6 positive families were consistent with autosomal-dominant inheritance. Expanded alleles ranged from 58 to 92 repeat units. Affected individuals showed adult-onset, slowly progressive, proximal-predominant pure lower motor neuron weakness with preserved bulbar and sensory function and no upper motor neuron signs. Expansions were rare in ALS cases (2/496, 0.40%) and controls (2/1,000, 0.20%).Discussion We identified LRP12 CGG repeat expansions in a substantial proportion of patients with slowly progressive, proximal-predominant pure lower motor neuron weakness not linked to 5q-SMA. These findings broaden the clinical spectrum of LRP12-related disease and support inclusion of LRP12 repeat-expansion analysis in the evaluation of genetically unresolved adult-onset lower motor neuron syndromes.
