CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
Abstract
Background Pathogenic variants in the CASK gene cause a broad spectrum of X-linked phenotypes ranging from microcephaly with pontine and cerebellar hypoplasia (MICPCH) to only mild intellectual disability (ID). Variable clinical pictures pose significant diagnostic challenges. Methods We conducted a retrospective observational study with longitudinal follow-up at a tertiary pediatric neurology center over a 10-year period (6,179 patients were hospitalized and evaluated). Since 2015, genetic testing using next-generation sequencing gene (NGS) panels, including CASK gene, was performed in patients with MICPCH and the first patient was confirmed through hereditary ataxia NGS panel. Two additional patients were identified among 105 children with suspected genetic neurodevelopmental disorders undergoing CentoNeuro panel (including 1,902 genes), which was available during a period (2023–2024). Clinical, neuroimaging, and genetic data were analyzed during follow-up. Results Two female patients carried de novo loss-of-function CASK variants and presented with MICPCH, progressive developmental impairment, abnormal muscle tone, postnatal growth retardation, and epilepsy in one case. The male patient carried an inherited likely pathogenic missense variant and exhibited severe ID, drug-resistant epilepsy, autistic features, and a cerebral palsy–like phenotype without microcephaly or pontocerebellar malformations. All patients demonstrated periods of developmental arrest or regression, suggesting non-linear developmental trajectories. Marked intrafamilial phenotypic variability was observed. Conclusions CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings. A cerebral palsy-like phenotype, postnatal growth retardation, and variable ID should raise suspicion for CASK-related disorders. Comprehensive genetic testing, including next-generation sequencing, is essential for accurate diagnosis.
To summarize the clinical and genetic characteristics of
DNM1L
-related disorders and explore genotype-phenotype correlations and prognosis.
We retrospectively analyzed clinical data from 18 children with
DNM1L
variants diagnosed between 2015 and October 2025. Combined with systematic literature review (2007-October 2025) to analyze reported
DNM1L
variant types and clinical phenotypes.
The cohort included 18 children (10 male, 8 female) with a median onset age of 3.5 years. Epilepsy occurred in 88.9% of patients, with 72.2% developing super-refractory status epilepticus; 66.7% had dystonia. Most patients exhibited brain MRI and EEG abnormalities. Eight novel pathogenic variants were identified (four missense, three frameshift, one compound heterozygous). Notably, eight patients with middle domain variants (primarily p.Arg403Cys) presented a novel “hemiconvulsion-hemiplegia-epilepsy syndrome” phenotype. At last follow-up, 83.3% had a modified Rankin Scale score ≥4, indicating severe disability and poor prognosis. Literatures review confirmed
DNM1L
variants are predominantly missense, with the middle domain as a hotspot. The p.Arg403Cys variant is recurrent and highly prevalent in the Chinese. Middle domain variants are more common in Asians, while GTPase domain variants are more frequent in Europeans. Missense variants in the middle domain correlated with higher rates of neurological dysfunction and mortality.
This study represents an extension of our earlier work by incorporating an additional 18 cases, which expands the genetic and phenotypic spectrum of
DNM1L
-related disorders. It identifies “hemiconvulsion-hemiplegia-epilepsy syndrome” as a distinct feature and potential prognostic indicator for middle domain variants. The established genotype-phenotype patterns, based on protein domains and ethnic differences, provide critical insights for precise diagnosis and management.
Han Xu, Chaolong Xu, Ying Zou et al.· Frontiers in Neurology· 0 citations
These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation and enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis.
E. Van Boxstael, C. Millevert, M. Hairabedian et al.· medRxiv· 0 citations
A retrospective multicenter case series of seven previously unreported individuals with heterozygous FBXW7 variants identified through clinical genetic testing expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance.
Salvatore Savasta, F. Comisi, G. Dell’Isola et al.· Journal of Neurodevelopmenta...· 0 citations
Background and Objectives ATP1A3-related disorders comprise an expanding group of ultra-rare neurologic conditions, classically including rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, accumulating reports suggest a broader and overlapping phenotypic spectrum. In this context, we established the ATP1A3 Study Group to comprehensively characterize the phenotypic and genotypic spectrum of ATP1A3-related disorders in a Brazilian cohort. Methods We conducted a multicenter, cross-sectional study of individuals with ATP1A3 variants. Cases were recruited across reference centers in 9 Brazilian states, with standardized extraction of demographic, genetic, neuroimaging, EEG, ECG, and clinical data. Variants were annotated using transcript NM_152296.5 (hg19). AlphaFold was used for structural visualization. Multiple correspondence analysis (MCA) was performed to explore symptom clustering. This study was approved by the Ethics Committee of Federal University of São Paulo (Approval No.: 82533124.0.0000.5505). Results A total of 41 patients with ATP1A3 variants were included. Seven phenotypic categories were represented: AHC (17/41), RDP (10/41), CAPOS (7/41), relapsing encephalopathy with cerebellar ataxia (RECA; 4/41), fever-induced paroxysmal weakness and encephalopathy (FIPWE; 1/41), developmental and epileptic encephalopathy 99 (DEE99; 1/41), and malformation of cortical development (MCD; 1/41). Two neonatal-onset cases (DEE99 and MCD) were fatal. We identified 22 distinct ATP1A3 variants, including 4 novel variants (p.Gln920His, p.Arg827Gly, p.Glu670Ala, and c.606+5G>T). Clinical overlap was substantial: Cognitive impairment and seizures occurred across all phenotypes; hypotonia was present in 6 of 7 main phenotypes; abnormal eye movements and fever-induced symptoms occurred in all except MCD; and paroxysmal symptoms were reported in all, except DEE99. MCA demonstrated no discrete clustering by classical phenotype, reinforcing the continuous nature of the ATP1A3 spectrum. ECG abnormalities were rare in our cohort (1/20). Discussion Our findings expand the clinical and genetic landscape of ATP1A3-related disorders and underscore major phenotypic overlap among classical syndromes. The results highlight the need for a unified diagnostic framework. This study also demonstrates the feasibility and scientific value of coordinated rare disease research in resource-limited settings.
Victor Rebelo Procaci, Raphael Pinheiro Camurugy da Hora, Anna Maria Gomes et al.· Neurology: Genetics· 0 citations
BACKGROUND
The traditional distinction between syndromic and nonsyndromic craniosynostosis has guided clinical management, but recent genomic advances suggest these categories represent a continuous spectrum rather than discrete entities. Data on genetic etiologies and long-term neurodevelopmental outcomes in Asian populations remain limited.
METHODS
The authors conducted a retrospective cohort study of 68 consecutive children diagnosed with craniosynostosis at a single tertiary center between January 2011 and November 2025. Genetic testing included whole-genome/whole-exome sequencing, targeted next-generation sequencing panels, and chromosomal microarray analysis (CMA). Neurodevelopmental assessments employed the Bayley Scales of Infant Development-III, Social Maturity Scale, Wechsler Intelligence Scales, and Beery-Buktenica Developmental Test of Visual-Motor Integration. Neurodevelopmental disorder (NDD) was defined as the presence of intellectual disability, autism spectrum disorder, or developmental language disorder; a secondary definition additionally included attention-deficit/hyperactivity disorder (ADHD).
RESULTS
Of 68 patients (40 males, 28 females), 39 (57.4%) underwent genetic testing, with pathogenic or likely pathogenic (P/LP) variants identified in 11 (28.2%; genetic-positive group). Identified variants involved chromatin modifiers (DNMT3A, NSD1, KMT2A), transcription factors (TCF12, SOX5), a signaling kinase (TAOK1), and a post-transcriptional regulator (TNRC6B); CMA additionally revealed pathogenic copy number variants (10q26.13-q26.3 deletion, 16p11.2 duplication, 15q11.2-q13.1 duplication, 2q37 deletion). In the primary analysis, NDD was identified in 8 of 11 patients (72.7%) in the genetic-positive group versus 10 of 28 (35.7%) in the genetic-negative group [P = 0.072; odds ratio (OR) 4.80, 95% confidence interval (CI) 1.03-22.29]. In the secondary analysis, including ADHD, NDD was significantly more prevalent in the genetic-positive group (9/11, 81.8% versus 11/28, 39.3%; P = 0.031; OR 6.95, 95% CI 1.26-38.44).
CONCLUSIONS
Comprehensive genetic testing yielded P/LP variants in 28.2% of tested craniosynostosis patients, revealing diverse molecular etiologies. Neurodevelopmental impairment was common and occurred even in genetically negative patients, supporting broad genetic evaluation together with systematic developmental surveillance for all affected children, independent of syndromic classification.
LEVEL OF EVIDENCE
Level III-Retrospective comparative study.
Sunyoung Joo, Jeon-Woong Kang, Si Won Yang et al.· The Journal of craniofacial...· 0 citations
Background Joubert syndrome (JS) is a rare neurodevelopmental ciliopathy characterized by a distinctive midbrain-hindbrain malformation, manifested by hypotonia, ataxia, developmental delay, and variable multisystem involvement. The condition exhibits marked clinical and genetic heterogeneity, with over 40 genes implicated to date. However, the mutational spectrum and phenotypic presentation of JS in Middle Eastern populations, where consanguinity is prevalent, remain poorly characterized. Methods We retrospectively reviewed whole-exome sequencing (WES) data from patients referred to the Comprehensive Medical Genetics Center, Shiraz, Iran, between 2019 and 2024. Patients harboring variants in JS-related genes were identified, and their clinical records were analyzed to establish genotype–phenotype correlations. Results A total of 21 cases with variants in JS-associated genes were identified. Neurological manifestations, including developmental delay/intellectual disability, speech defects, seizures, and motor impairment, were the most prevalent findings. Vision problems, renal involvement and polydactyly were also present. Molecular analysis revealed variants in 14 distinct genes, with AHI1 being the most frequently mutated (3 cases), followed by KIAA0586, CSPP1, KIAA0556, CC2D2A, and TMEM67. Eight cases carried pathogenic or likely pathogenic variants, while 12 cases had variants of uncertain significance (VUS), highlighting the diagnostic challenges in this genetically heterogeneous condition. Conclusion This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies. The high rate of consanguinity in this cohort likely contributes to the enrichment of autosomal recessive forms. Further functional studies are warranted to clarify the pathogenicity of the numerous VUS identified, which will improve genetic counseling and prenatal decision-making for affected families.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations