Deciphering the Role of LNX2 as a Potential Contributor to Neurodevelopmental Disorders

CMIP as a novel candidate gene for neurodevelopmental and neuropsychiatric 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.

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

This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.

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.

Intrafamilial Variability in NRXN1-Associated Neurodevelopmental Disorders: Clinical and Genetic Insights from a Family Case Study with Literature Review

The concept that NRXN1 deletions alone do not determine clinical outcome but rather act within a broader genetic and biological context is supported, whereby NRXN1 deletions act as susceptibility factors whose phenotypic consequences are shaped by additional genetic and modifying influences.

Reclassification of the GRIA3 splice-site variant in an X-linked family with intellectual disability and psychiatric symptoms

The GRIA3 gene is located on the X chromosome and encodes a subunit (GluR3) of the a-amino-3- hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). The pathogenic variants of GRIA3 are mostly associated with neurodevelopmental disorders. Patients were overwhelmingly male and presented mainly with intellectual disability, dystonia, epilepsy and other symptoms. In this study, we reported a pedigree that carried a novel splicing site variant of GRIA3 (c.268 + 1G>C) by whole exome sequencing (WES) and co-segregation analysis. Three affected family members (two males and one female) not only showed intellectual disability but also presented significant psychiatric symptoms and spatial memory deficits. The minigene assay further confirmed that this variant lead to exon 2 skipping. According to ACMG guidelines, We reclassified previously variant of unknown significance (VUS) into “likely pathogenic” through co-segregates analysis and minigene assay. It is worth noting that, unlike previous reports, our patients mainly manifested as intellectual disability combined with psychiatric symptoms, expanding the known phenotypic spectrum of GRIA3 gene. Moreover, this variant is the first reported, enriching the database and providing additional evidence to support genetic counselling and prenatal diagnosis.