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Results for “Mendelian neurodevelopmental disorder”

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PubMed2026

A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental/neurodegenerative syndrome demonstrates the role of histone H3.3 in chromatin dynamics, neuronal differentiation, and maturation.

BACKGROUND: Bryant-Li-Bhoj neurodevelopmental syndrome (BLBS) is neurogenetic disorder caused by variants in H3-3A and H3-3B, the two genes that encode histone H3.3. Ninety-nine percent of individuals with BLBS show developmental delay/intellectual disability, but the mechanism by which variants in H3.3 result in these phenotypes is not yet understood, limiting the therapeutic interventions available to individuals living with BLBS. METHODS: Here, we investigate how one BLBS-causative variant, H3-3B p.Leu48Arg (L48R), affects neurodevelopment using an induced pluripotent stem cell model differentiated to 2D neural progenitor cells (NPCs), 2D forebrain neurons (FBNs), and 3D dorsal forebrain organoids (DFBOs). We employ a multi-omic approach in the 2D models to quantify the resulting changes in gene expression and chromatin accessibility. We used immunofluorescence (IF) staining to define the identities of cells in the 3D DFBOs and whole-cell patch clamp to investigate the electrophysiological properties of neurons in DFBOs. RESULTS: In the 2D systems, we found dysregulated gene expression and chromatin accessibility affecting neuronal fate, adhesion, neurotransmission, and excitatory/inhibitory balance. Immunofluorescence of DFBOs corroborated altered proportions of radial glia and mature neuronal populations. Patch clamp recordings revealed decreased electrical activity in neurons from L48R DFBOs compared to control DFBOs. CONCLUSIONS: These data provide the first mechanistic insights into the pathogenesis of BLBS from a human-derived model of neurodevelopment, which suggest that H3.3 L48R increases H3-3B expression, resulting in the hyper-deposition of H3.3 into the nucleosome, which underlies changes in gene expression and chromatin accessibility. Functionally, this causes dysregulation of cell adhesion, neurotransmission, and the balance between excitatory and inhibitory signaling. These results are a crucial step towards preclinical development and testing of targeted therapies for this and related disorders.

Histones↗

PubMed2025

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson Syndrome.

Sex-specific penetrance in autosomal dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1 R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety and hypotonia. Orchiectomy unmasks a growth deficiency phenotype in male Chd1 R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open novel avenues to understand the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

CHD1↗

PubMed2026

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.

Male↗

PubMed2026

Mendelian disorders of the epigenetic machinery: a decade of insights into the molecular basis.

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.

Humans↗

PubMed2025

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans↗

PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗

PubMed2023

De novo variants in MRTFB have gain-of-function activity in Drosophila and are associated with a novel neurodevelopmental phenotype with dysmorphic features.

PURPOSE: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder. METHODS: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB. RESULTS: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFBR104G and MRTFBA91P variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton. CONCLUSION: The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function.

Animals↗

PubMed2025

Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder.

PURPOSE: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date. METHODS: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning. RESULTS: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We found an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder. We demonstrate XPO1 functions in development by ubiquitous and neuron-specific knockdown in Drosophila. GABAergic neuron specific knockdown flies demonstrated impaired habituation. CONCLUSION: Our results establish XPO1 as a novel dominant monogenic neurodevelopmental disorder gene and demonstrate a central role for XPO1 in development.

Exportin 1 Protein↗

PubMed2026

Developmental genetic determinants of the human cerebrospinal fluid-ventricular system.

Primary enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the "hand-in-glove" development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Humans↗

PubMed2024

Maternal COVID-19 infection associated with offspring neurodevelopmental disorders.

Maternal COVID-19 infection increases the incidence of neurodevelopmental disorders (NDDs) in offspring, although the underlying mechanisms have not been elucidated. This study demonstrated that COVID-19 infection during pregnancy disrupted the balance of maternal and fetal immune environments, driving alterations in astrocytes, endothelial cells, and excitatory neurons. A risk score was established using 47 unique genes in the single-cell transcriptome of gestational mothers. The high risk score in CD4 proliferating T cell level served as an indicator for increased risk of offspring NDDs. Summary-based Mendelian randomization and phenome-wide association study analyses were conducted to identify the causal association of the transcriptional changes with the increased risk of offspring NDDs. Additionally, 10 drugs were identified as potential therapeutic candidates. Our findings support a model where the maternal COVID-19 infection changed the levels of CD4 proliferating T cells, leading to the alterations of astrocytes, endothelial cells, and excitatory neurons in offspring, contributing to the increased risk of NDDs in these individuals.

Humans↗

PubMed2025

Multi-omics reveals cross-tissue regulatory mechanisms of autism risk loci via gut microbiota-immunity-brain axis.

Autism Spectrum Disorder (ASD) involves a multi-system interaction mechanism among genetics, immunity, and gut microbiota, yet its regulatory network remains undefined. This study conducted a meta-analysis on Genome-Wide Association Study data from four independent ASD cohorts to identify potential genetic loci. By integrating Polygenic Priority Score, brain region, and brain cell eQTL enrichment analyses, and combining summary-data-based Mendelian Randomisation (SMR) analyses of brain cis-eQTL and mQTL, bidirectional Mendelian Randomisation analyses of 473 gut microbiota, and SMR analysis of blood eQTL, SNPs such as rs2735307 and rs989134 with significant multi-dimensional associations were identified. These loci exert cross-tissue regulatory effects by participating in gut microbiota regulation, involving immune pathways such as T cell receptor signal activation and neutrophil extracellular trap formation, as well as cis-regulating neurodevelopmental genes (HMGN1 and H3C9P), or synergistically influencing epigenetic methylation modifications to regulate the expression of BRWD1 and ABT1. The cross-scale evidence chain constructed in this study provides a theoretical foundation for precision medicine research in ASD, holding promise to advance the development of innovative therapeutic strategies.

Autism spectrum disorder↗

PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗

PubMed2025

A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

PURPOSE: Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. METHODS: Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. RESULTS: Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. CONCLUSION: We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.

Humans↗