Background: Developmental and Epileptic Encephalopathy (DEE) is a severe and heterogeneous neurological disorder in infancy/early childhood. DEE’s genetic and phenotypic variability complicates diagnosis and treatment. This retrospective study aimed to identify genetic variants and explore genotype–phenotype correlations in children with DEE using a targeted epilepsy gene panel (TGP) and Whole Exome Sequencing (WES). Patients and Methods: Medical records of children who underwent custom-designed 55-gene TGP and WES were reviewed. The diagnostic yield of each method was determined based on the detection of pathogenic (P) and likely pathogenic (LP) variants. Results: A total of 129 patients (66 males, 63 females) underwent TGP, which identified P/LP variants in 29 cases (22.48%). Variants were detected in SCN1A, KCNQ2, STXBP1, CDKL5, PCDH19, PLCB1, WWOX, SCN2A, FGF12, HCN1, SCN8A, and SLC35A2. WES further identified several variants in children with West syndrome. A TSC1 variant was detected in a patient without cutaneous stigmata of tuberous sclerosis complex. The NALCN variant in a patient was linked to Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 1. A CTBP1 variant associated with extremely rare Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome was detected in another patient. A PIEZO2 variant—associated with Marden–Walker syndrome—was found in a child with Early Infantile Developmental and Epileptic Encephalopathy. Conclusions: These findings highlight the extensive genetic heterogeneity and phenotypic variability of DEE. WES demonstrates substantial value in identifying novel gene-disease associations and may be considered as a first-tier diagnostic tool in epilepsy and DEE.

Background Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses.Methods In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis.Results Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively.Conclusion Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Omodysplasia is an extremely rare short-limb skeletal dysplasia characterized by severe micromelic dwarfism with predominantly rhizomelic shortening of the upper and lower limbs. Type 1 omodysplasia, alsoknown as autosomal recessive omodysplasia, is caused by a mutation in the GPC6 gene. This is the first caseof a patient with schizophrenia genetically diagnosed with omodysplasia type 1. A 27-year-old, universitygraduate, bilingual, single white woman was brought to the emergency psychiatry clinic with psychomotor agitation, anxiety, persecutory delusions, and hallucinations. On the basis of the patient’s background,she was diagnosed with omodysplasia type 1 in early childhood. In addition, she was diagnosed withschizophrenia 8 years ago. Informed consent was obtained from the patient and her mother, who had anadvance directive. Schizophrenia is a neurodevelopmental disorder caused by both genetic and environmental factors. GPC6 is also associated with formal thought disorder (FTD), which is a common symptom ofschizophrenia. GPC6 gene mutation in FTD is located on chromosome 13, such as that of autosomal recessive omodysplasia. Although this case could be coincidental, it may contribute to current genetic studiesthat have an important place in the etiology of schizophrenia.Cite this article as: Poyraz E, Firidin S, Göverti D, Ulu B, Bülbül A, Özer T. Autosomal recessive omodysplasia (GPC6-related)with treatment-resistant schizophrenia. Neuropsychiatr Invest. 2025, 63, 0015, doi:10.5152/NeuropsychiatricInvest.2025.25015.

Background. Congenital disorders of glycosylation (CDG) represent a group of inherited metabolic diseases characterized by multisystem involvement. SLC35A2-CDG (OMIM #300896) is a rare X-linked subtype resulting from pathogenic variants in the SLC35A2 gene, which encodes the UDP-galactose transporter. Approximately 70 cases have been documented, predominantly presenting with early-onset epilepsy, developmental delay, hypotonia, and dysmorphic features. Phenotypic variability remains incompletely characterized, and novel features continue to expand the clinical spectrum. Case Presentation. We report a 6-year-old girl with SLC35A2-CDG harboring a novel de novo heterozygous frameshift variant (NM_005660.3: c.105_106insCG, p.K36Rfs*6). The patient presented with epileptic spasms, severe global developmental delay, hypotonia, and distinctive dysmorphic features including strabismus and inverted nipples. Notably, she exhibited bilateral patellar luxation and perineal dysmorphism with a shortened anogenital distance, features that have not been previously associated with SLC35A2-CDG. Additional findings included a thin corpus callosum, a pineal cyst, right-sided aortic arch, bilateral vesicoureteral reflux, and central hypothyroidism. Oral D-galactose supplementation was initiated and resulted in subjective improvements in language comprehension, pain responsiveness, and motor function, although no improvement in seizures was observed. Conclusions. This casa may expand the phenotypic spectrum of SLC35A2-CDG by describing bilateral patellar luxation and perineal dysmorphism as potentially novel clinical features, along with a previously unreported pathogenic variant. Recognition of such unique features is crucial for improving our clinical understanding of this rare disorder, guiding differential diagnosis, and contributing to a more refined characterization of genotype–phenotype correlations.