Cerebellar ataxias (CAs) comprise a group of rare, neurological disorders characterized by extensive phenotypic and genetic heterogeneity. The core clinical feature is the cerebellar syndrome, which is often accompanied by other neurological or non-neurological signs. In the last 30 years, our understanding of the CA etiology has increased significantly, and numerous ataxia-associated genes have been discovered. Conventional variants or tandem repeat expansions, localized in the coding or non-coding DNA sequences, lead to hereditary ataxia, which can display different patterns of inheritance. Advances in molecular techniques have enabled a rapid and cost-effective detection of causative variants in a significant number of CA patients. However, despite performing extensive investigations, a definite diagnosis is still unknown in the majority of affected individuals. In this review, we discuss the major advances in the genetics of CAs over the last 30 years, focusing on the impact of next-generation sequencing on the genetic landscape of childhood- and adult-onset CAs. Additionally, we outline possible directions for further genetic research in hereditary and sporadic CAs in the era of increasing application of whole-genome sequencing and genome-wide association studies in various neurological disorders.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare hereditary ataxia, characterized by the triad of early-onset cerebellar ataxia, peripheral sensorimotor neuropathy and lower limb spasticity. Although ARSACS is increasingly reported worldwide, we present the first Polish family with a comprehensive clinical and neuropsychological assessment, harboring two novel mutations in the SACS gene. Our results demonstrate the variability in cognitive and behavioral profiles in ARSACS, which is in line with other heredodegenerative ataxias. One should be aware of ARSACS in cases of autosomally recessive inherited ataxias without common mutations.

Alternative splicing (AS) is crucial for cell‐type‐specific gene transcription and plays a critical role in neuronal differentiation and synaptic plasticity. De novo frameshift variants in NOVA2, encoding a neuron‐specific key splicing factor, have been recently associated with a new neurodevelopmental disorder (NDD) with hypotonia, neurological features, and brain abnormalities. We investigated eight unrelated individuals by exome sequencing (ES) and identified seven novel pathogenic NOVA2 variants, including two with a novel localization at the KH1 and KH3 domains. In addition to a severe NDD phenotype, novel clinical features included psychomotor regression, attention deficit‐hyperactivity disorder (ADHD), dyspraxia, and urogenital and endocrinological manifestations. To test the effect of the variants on splicing regulation, we transfected HeLa cells with wildtype and mutant NOVA2 complementary DNA (cDNA). The novel variants NM_002516.4:c.754_756delCTGinsTT p.(Leu252Phefs*144) and c.1329dup p.(Lys444Glnfs*82) all negatively affected AS events. The distal p.(Lys444Glnfs*82) variant, causing a partial removal of the KH3 domain, had a milder functional effect leading to an intermediate phenotype. Our findings expand the molecular and phenotypic spectrum of NOVA2‐related NDD, supporting the pathogenic role of AS disruption by truncating variants and suggesting that this is a heterogeneous condition with variable clinical course.

Background: NKX2‐1 –related disorders result from heterozygous variants in NKX2‐1 , a gene crucial for brain, lung, and thyroid development. Although movement disorders, hypothyroidism, and neonatal respiratory distress are recognized, the full phenotype and genotype–phenotype relationships remain incompletely defined. Objectives: To delineate neurological, respiratory, and endocrine features across ages, characterize movement disorder trajectories – particularly chorea – and explore genotype–phenotype associations with clinical relevance. Methods: We conducted a multicenter, cross‐sectional study recruiting participants through referral clinicians and European networks. Standardized clinical and genetic data were captured in an electronic database and analyzed with descriptive and inferential statistics. Results: Sixty‐eight individuals (37 female; median age 16 years, range 2–60 years) were included. Motor delay was the commonest presenting feature (~60%); neonatal respiratory distress syndrome occurred in one‐third of cases. The brain–lung–thyroid triad was present in almost half. Chorea affected over 90% and began in early childhood; it was more frequent with single nucleotide variants than with deletions. Deletions are associated with better gross motor function. Frameshift or nonsense variants showed greater respiratory involvement, and variants in the exon‐3 homeobox region were associated with age‐related reduction of chorea. Neonatal respiratory distress predicted later respiratory symptoms. Greater abnormal involuntary movement severity correlated with poorer manual and gross motor function. Hypotonia and untreated hypothyroidism are associated with more severe chorea. Psychiatric comorbidity occurred in over one‐third of cases, mainly attention‐deficit/hyperactivity symptoms. Conclusions: This largest cohort to date shows early neurological onset, genotype‐specific outcomes, and frequent psychiatric comorbidity in NKX2‐1 ‐related disorders, refining clinical expectations and supporting genotype‐informed diagnosis, counseling, and management. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Introduction: Epilepsy is one of the commonest diseases in children, characterized by extensive phenotypic and genetic heterogeneity. This study was conducted to determine the diagnostic utility and to identify novel clinical and therapeutic implications of genetic testing in pediatric patients with epilepsy.Methods: Large multigene panel and/or exome sequencing was performed in 127 unrelated Polish and Ukrainian patients with suspected monogenic epilepsy. Diagnostic yields were presented for five phenotypic subgroups, distinguished by seizure type, electroencephalographic abnormalities, anti-seizure treatment response, and neurodevelopmental deficits.Results: A definite molecular diagnosis was established in 46 out of 127 cases (36%). Alterations in six genes were detected in more than one patient: SCN1A, MECP2, KCNT1, KCNA2, PCDH19, SLC6A1, STXBP1, and TPP1, accounting for 48% of positive cases. 4/46 cases (8.7%) were mosaic for the variant. Although the highest rates of positive diagnoses were identified in children with developmental delay and generalized seizures (17/41, 41%) and in developmental end epileptic encephalopathies (16/40, 40%), a monogenic etiology was also frequently detected in patients with solely focal seizures (10/28, 36%). Molecular diagnosis directly influenced anti-seizure management in 15/46 cases.Conclusion: This study demonstrates the high diagnostic and therapeutic utility of large panel testing in childhood epilepsies irrespective of seizure types. Copy number variations and somatic mosaic variants are important disease-causing factors, pointing the need for comprehensive genetic testing in all unexplained cases. Pleiotropy is a common phenomenon contributing to the growing phenotypic complexity of single-gene epilepsies.