Jul 2026· Journal of genetics and genomics = Yi chuan xue bao· 0 citations· 120 references
Medicine
TL;DR
Four major themes are identified, encompassing genetic modifiers, epigenetic modifications, mosaicism, and environmental factors that may act independently or interactively to influence pathogenic burden and functional network balance, ultimately determining whether a pathogenic mutation manifests clinically.
Abstract
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.
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.
Varada Vidya Rani, Suryanarayana Reddy Kovvuri, D. Arya· Genetics and Molecular Resea...· 0 citations
Exome sequencing (ES) has become a primary tool for diagnosing neurodevelopmental disorders (NDDs), yet the interpretation of genetic variants in large, heterogeneous cohorts presents significant challenges that automated pipelines often fail to resolve. This study showcases the complexities and novel findings derived from a decade-long analysis of 419 Italian NDD patient-parent trios. While ES established a molecular diagnosis in 36.5% of cases (53.8% in syndromic presentations), our investigation moves beyond diagnostic yield to highlight the critical value of manual curation integrated with deep phenotyping. We demonstrate how this rigorous approach uncovers complex disease mechanisms, revealing that variants initially misclassified as missense or stop-gain are, in fact, pathogenic splicing defects confirmed by functional analysis. Furthermore, we resolve the paradox of pathogenic truncating PPM1D variants in control databases by demonstrating their somatic mosaic nature, a crucial insight for population data interpretation. Our work also refines gene-disease correlations by challenging the established role of MID2 in NDDs, providing further evidence for DSCAM as a high-confidence risk gene, and expanding the known phenotypic spectrum of disorders, such as a novel GNAI2-related syndrome lacking expected immune dysfunction. This study underscores that navigating the complexities of large NDD cohorts requires a detailed, expert-driven approach to not only enhance diagnostic yield but also to advance our fundamental understanding of rare disease genetics.
Simona Cardaropoli, Lisa Pavinato, Slavica Trajkova et al.· Human Genetics· 0 citations
Chorea is a symptom of numerous pathophysiologically and clinically heterogeneous genetic conditions. A number of developments have been made in this field over the last years linked to improved genomic testing, large cohort collaborations and improved understanding of the molecular mechanisms. This review aims to provide an update on the new genetic conditions and phenotypes linked to chorea disorders, their modification factors and pathophysiological background. Several novel genetic conditions have been linked to chorea over the last 3 years, including mutations in FTH1, NAA60, ACBD6 or TOR1AIP2. Also, novel phenotypes have been established and linked to chorea, such as Adult-onset Neurodegeneration in Nucleotide Excision Repair Disorder (NERD-ND). Major advances have been made in understanding of the pathophysiological role of somatic instability in HD. Striatal pallidal neurons (SPNs) with 150–500 + CAG repeats seem to lose positive and then negative features of neuronal identity, de-repress senescence/apoptosis genes, ultimately leading to cell death. Improved recognition of the genetic background of chorea leads to more effective diagnostic processes, better prognostication and improved personalized treatment. The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful. This has potential major therapeutic implications not only in HD but also in other neurological repeat expansion disorders.
M. Ostrožovičová, M. Škorvánek· Current Neurology and Neuros...· 0 citations
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.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
The Mendelian disorders of the Epigenetic Machinery (MDEMs), or Chromatinopathies, are now understood to be a collectively common cause of childhood neurodevelopmental delays and intellectual disability. In the past decade, the chromatin and gene expression consequences of heterozygous chromatin regulator disruption have been investigated in various disease models, yielding insights into the molecular pathogenesis of MDEMs. In this review, we highlight some of these results - drawing upon studies of representative MDEMs - together with potential unifying concepts. We propose that MDEMs are characterized by distributed, often subtle chromatin and gene expression perturbations, which impact diverse cellular pathways and processes and are frequently shared between distinct disorders. In this sense, they occupy an intermediate space between classical monogenic disorders and complex traits. We propose potential explanations for the variable expressivity in MDEMs and conclude by considering how technological advances can now enable a deeper and more precise mechanistic characterization of this important Mendelian disease group.
Leandros Boukas, Hans T Bjornsson· Epigenomics· 0 citations
Neurodevelopmental Disorders (NDDs) arise when a pathogenic gene mutation disrupts an
individual’s brain development, often resulting in symptoms such as epilepsy, motor impairments, and
intellectual disability. Historically, NDDs have been managed primarily through pharmacological and
behavioral therapies that alleviate symptoms but do not address the underlying genetic causes. Recent
advances in genomic medicine, particularly the development of Clustered Regularly Interspaced Short
Palindromic Repeats (CRISPR)-based technologies, have created the opportunity to directly target
disease-causing genes. The versatility of CRISPR has enabled the development of multiple editing and
regulatory modalities, allowing increasingly precise control of gene expression. Preclinical studies
in rodent models suggest that CRISPR-mediated epigenetic reactivation may be an effective strategy
for treating monogenic NDDs by restoring gene function without permanently altering the DNA
sequence. While these approaches show promise, significant challenges related to delivery, safety, and
ethical considerations remain. Despite these controversies surrounding the use of CRISPR, it remains
a prospective candidate in improving the management of NDDs in the future. This review evaluates
the potential of CRISPR-based editing as a therapeutic strategy for monogenic NDDs and evaluates the
limitations that must be addressed before its widespread application in human patients.
Julia Mulles· American Journal of Student...· 0 citations