A novel mutation in SETD1A is associated with early-onset epilepsy—a rare case report

RFX3 Pathogenic Variants as a Rare Cause of Infantile Epileptic Spasms Syndrome

This case expands the clinical spectrum associated with RFX3 variants, supporting a potential role in IESS and early neurodevelopmental disruption, and highlights the relevance of including RFX3 in the genetic evaluation of patients with IESS and co-occurring neurodevelopmental disorders.

A case report of a novel de novo variant in PPP2CA causing a neurodevelopmental disorder and epilepsy

The findings support the pathogenicity of this variant and further expand the pathogenic variant spectrum of the PPP2CA gene, and the observed genotype–phenotype correlation provides valuable information for prognosis and genetic counseling.

Expanding clinical variability in FBXW7-related neurodevelopmental disorder: a multicenter case series

Heterozygous variants in FBXW7 have recently been recognized as a cause of a rare neurodevelopmental disorder with variable developmental delay, neurological manifestations, and multisystem involvement. The breadth of clinical variability and penetrance remains incompletely defined. We report a retrospective multicenter case series of seven previously unreported individuals (five males, two females) with heterozygous FBXW7 variants identified through clinical genetic testing, aged 5–9 years at last evaluation (median 6 years). Six variants occurred de novo and one was inherited. Neurodevelopmental involvement was present in six individuals and was characterized by global developmental delay and language impairment; hypotonia was observed in all seven. Formal intellectual disability was documented in four cases, while one individual showed preserved cognitive functioning with predominant behavioral difficulties. Epileptic seizures occurred in four individuals, whereas three had no history of epilepsy. Brain MRI was available for six individuals and was normal in four, whereas two showed structural anomalies involving the corpus callosum. Extracerebral features were variably reported, most commonly constipation and recurrent respiratory/otolaryngological infections. Comparison with previously reported individuals confirmed the core neurodevelopmental phenotype and further refined the spectrum. This case series expands the phenotypic spectrum associated with FBXW7-related neurodevelopmental disorder and highlights variable expressivity and incomplete penetrance, including clinically relevant variants presenting with mild or atypical phenotypes. These findings support considering FBXW7 across a broad range of neurodevelopmental presentations and inform genetic counseling.

Clinical heterogeneity and diagnostic challenges in CASK-related neurodevelopmental disorders: a longitudinal observational study

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.

Novel Homozygous Pathogenic Variant in DNAJC6 Causes Rapid Progressive Parkinsonism.

BACKGROUND Biallelic variants in DNAJC6 cause PARK-DNAJC6 (historically referred to as PARK19), a rare autosomal recessive juvenile-onset dystonia-parkinsonism syndrome. Neurodevelopmental delay or regression, epilepsy, movement disorders, and psychiatric symptoms are also present. Progression is fast with frequent bulbar, gastrointestinal involvement and early loss of ambulation. CASES We report two siblings (17 and 14 years) harboring a novel homozygous nonsense variant in DNAJC6, p.Cys325*, not previously described in the medical literature and absent from population databases. The variant is predicted to truncate the protein, supporting a loss-of-function mechanism consistent with the gene's disease biology. Both patients exhibited developmental regression, parkinsonism with dystonia, cognitive decline, dysphagia, and marked sialorrhea, with severe, accelerated functional deterioration. Levodopa produced only mild benefit; in the older sibling, dose escalation provoked an adverse reaction with sustained upgaze/ophthalmoparesis, opisthotonus, and hypertension. LITERATURE REVIEW We found 23 previously reported DNAJC6 patients, most with early-onset parkinsonism with variable levodopa responsiveness, frequent developmental and psychiatric comorbidity, and prominent bulbar features. CONCLUSIONS The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression. DNAJC6 should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.

A novel CHMP2B variant of uncertain significance in a patient with apathy, hyperorality, and mild language impairment.