Jul 2026· Genetics and Molecular Research· 0 citations· 35 references
TL;DR
The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
Abstract
Pediatric neurological disorders represent a heterogeneous group of conditions characterized by early-onset impairment in cognitive, motor, and behavioral functions, with significant lifelong consequences. This systematic review aims to synthesize current evidence on the genetic and molecular mechanisms underlying these disorders. A comprehensive literature search was conducted across major databases following PRISMA 2020 guidelines, resulting in the inclusion of 15 high-quality studies. The findings highlight a predominantly de novo–driven genetic architecture, with key contributions from rare variants and copy number variations affecting neurodevelopmental pathways. At the molecular level, consistent disruptions were identified in synaptic signaling, ion channel regulation, and excitatory–inhibitory balance, indicating strong pathway-level convergence despite gene-level heterogeneity. These mechanisms were found to underlie major disorder categories, including autism spectrum disorder, epileptic encephalopathies, and intellectual disability. The review further emphasizes the importance of genotype–phenotype relationships, although variability in clinical expression remains a challenge. Advances in next-generation sequencing have significantly improved early diagnosis and facilitated the transition toward precision medicine approaches. However, gaps remain in translating molecular findings into targeted therapies due to limited functional validation and clinical trials. The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
This review synthesizes contemporary insights into the genetic and molecular pathophysiology of seizures and epilepsy, with emphasis on mechanisms that destabilize excitation–inhibition balance, promote epileptogenesis, and drive pharmacoresistance and supports more refined approaches to epilepsy classification and future precision medicine strategies.
Mohammad Reza Seyedtaghia, Jina Babanzadeh, Marcello Scala et al.· Epilepsia Open· 0 citations
Neurogenetic disorders have been recognized clinically for decades, and advances in clinical and genetic studies have identified more than 1700 monogenic causes of neurological diseases. Various types of mutations, including missense, truncating, and repeat expansions, have been reported in patients with neurogenetic disorders. It is now recognized that incomplete penetrance is common, with some individuals carrying disease-causing mutations remaining clinically unaffected. However, there is currently no comprehensive conceptual framework to categorize or explain these observations. Here, we review and integrate decades of evidence on incomplete penetrance in neurogenetic disorders to clarify its biological and mechanistic bases. Accordingly, four major themes are identified, encompassing genetic modifiers, epigenetic modifications, mosaicism, and environmental factors. These factors may act independently or interactively to influence pathogenic burden and functional network balance, ultimately determining whether a pathogenic mutation manifests clinically. Based on these insights, we highlight emerging perspectives and propose future research to fill gaps in our understanding. A deeper understanding of incomplete penetrance will be essential for generating genetic insights to support more effective genetic counseling, therapeutic interventions, and disease prevention in neurogenetic disorders.
Jiao-Jiao Xu, Dian-Fu Chen, Zhi-Ying Wu· Journal of genetics and geno...· 0 citations
BACKGROUND
Autism spectrum disorder (ASD) is a neurodevelopmental condition including incorrect functioning in communication, social interaction, and repetitive behavior. Global prevalence is estimated as 1-2%, with a predominance of men. Different pre- and perinatal, environmental, immunological, neurobiological, genetic, and epigenetic factors are involved in the etiology of ASD. The study aims to analyze genetic abnormalities in patients with ASD according to data from the current literature.
MATERIALS AND METHODS
Studies available in the PubMed and Google Scholar databases were chosen through a literature search. Only papers published from 2020, available as full-text publications in English, with studies conducted on humans, original papers, or meta-analyses were included.
RESULTS AND DISCUSSION
The following types of genetic variation were identified: copy number variants, larger insertions, inversions, uniparental disomies, tandem repeat expansions, common single nucleotide polymorphisms, single nucleotide variants, short insertions/deletions, and mitochondrial variants. Epigenetic factors, like histone modifications, deoxyribonucleic acid (DNA) methylation, and micro ribonucleic acid might play an important role in ASD predisposition. Genes identified in the review were mainly involved in neurodevelopment, synaptic formation, neuronal migration, neurotransmission, glial proliferation, ubiquitination, chromatin remodeling, or transcription. ASD is described as a component of the phenotype in fragile X syndrome, tuberous sclerosis complex, neurofibromatosis type 1, Angelman, Phelan-McDermid, Smith-Lemli-Opitz syndromes, and chromosome trisomies. Current guidelines for genetic diagnosis of ASD recommend performing directed genetic studies in the first line (like multiplex ligation-dependent probe amplification - MLPA, analysis of FMR1 gene), in case of a negative result, chromosomal microarray as a routine method, then next-generation sequencing (NGS) panel testing, WES (whole exome sequencing), or even WGS (whole genome sequencing) as the last test.
CONCLUSIONS
Wider access to modern diagnostic methods has increased the number of ASD patients in whom the genetic etiology of the disorder has been uncovered. Knowledge of the genetic background would be applicable in the diagnosis, prevention, prognosis, and individualized treatment.
G. Ręka, Katarzyna Wojciechowska, Monika Lejman· BMC Medical Genomics· 0 citations
A high genetic predisposition for neuropsychiatric disorders, such as schizophrenia and autism spectrum disorders (ASDs), is 22q11.2 deletion syndrome (22q11DS), caused by a hemizygous microdeletion in the q-arm of human chromosome 22. The deletion most often spans a 3Mb region, with variable breakpoints ranging from 1.5-3Mb. Experimental studies on 22q11DS have revealed the pathophysiology of neuropsychiatric disorders and also identified various interventional and rescue strategies. Herein, we review these strategies by grouping the studies into three main mechanistic categories: (i) microRNA (miR)-mediated, (ii) mitochondrial, and (iii) neural circuit deficits in polygenic deletion, and also briefly describe a few other monogenic mechanisms implicated. Haploinsufficiency of Dgcr8, a 22q11DS gene involved in miR processing, forms the center of miR-mediated mechanisms and rescuing consequent pathophysiology rely on age-dependent, brain-region specific or global replenishment of miRs or their targets. Seven genes in the 22q11.2 genomic region encode mitochondrial proteins and approaches to mitigate these gene deficiencies concentrate on the respective mitochondrial functions affected. We briefly describe other potential monogenic mechanisms for intervention including transcriptional regulation, synaptic release, catecholamine metabolism, and cell adhesion, represented by Tbx1, Sept5, COMT, Arvcf, and Cldn5. We also give examples of how the multifaceted pathophysiological mechanisms and rescue strategies can have convergent effects at the molecular, synaptic, cellular and circuit levels. Based on the experimental interventions identified in the 22q11DS studies, we inform on the supportive therapies possible now and the future potential of curative interventions.
P. Devaraju· Progress in neurobiology· 0 citations
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.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
Autism spectrum disorders (ASD) and speech disorders are neurodevelopmental disorders whose etiology involves intricate genetic and molecular mechanisms. In recent years, the FOXP2-CNTNAP2 pathway has been identified as playing a crucial role in language development and neural function. Aberrant expression or mutation within this pathway is closely associated with the pathogenesis of ASD and speech disorders. Nevertheless, the specific regulatory mechanisms of this pathway and its pathological role in these diseases have not been fully clarified. Therefore, a systematic review of existing research is urgently required to elucidate its molecular underpinnings. An in-depth analysis of the genetic and molecular mechanisms of the FOXP2-CNTNAP2 pathway will not only contribute to understanding the pathogenesis of ASD and speech disorders but also offer potential molecular markers for diagnosing related conditions. Moreover, it provides a theoretical foundation for developing targeted therapeutic strategies. Additionally, this research may offer a novel perspective for studying genetic regulatory networks in neurodevelopment, holding significant scientific value and clinical translation potential.
Fanglin Song, X. Li, Cheng Cheng et al.· Journal of neural transmissi...· 0 citations