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.
“hemiconvulsion-hemiplegia-epilepsy syndrome” is identified as a distinct feature and potential prognostic indicator for middle domain variants in DNM1L variants, which are predominantly missense, with the middle domain as a hotspot.
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
The results highlight the need for a unified diagnostic framework for ATP1A3-related disorders and demonstrate 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
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.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations