SEARCH · PubMed Health

Results for “Neurodevelopmental disorders”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

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

Complex genotype-phenotype relationships in neurodevelopmental disorders.

With the advent of sequencing technologies in recent years, hundreds of high-confidence risk genes have been implicated in neurodevelopmental disorders (NDDs). However, individuals carrying pathogenic variants in the same gene frequently exhibit diverse clinical presentations, including varied symptoms and diagnoses. We propose that this heterogeneity arises from different interacting factors that modulate the phenotypic outcomes of pathogenic variants, including variant-level features, modifying variation across the genome, prenatal and early-life environmental exposures, and developmental noise. Resolving these factors requires integrative approaches that combine population-scale genetics and functional genomics with environmental monitoring and quantitative assessments of stochastic developmental variation. Advancing our understanding of these factors is critical to elucidating the etiology of NDDs and improving diagnostic and personalized therapeutic strategies.

Humans↗

PubMed2025

Sex differences in the developing human cortex intersect with genetic risk of neurodevelopmental disorders.

Autism is highly heritable and diagnosed more frequently in males than females. To identify neurodevelopmental processes that might present sex-biased vulnerability, we generated transcriptomic and epigenomic profiles of cell types present in the prenatally developing human cerebral cortex of 27 males and 21 females. By intersecting sex-biased molecular signatures and genes with de novo mutations in male and female autistic probands, we reveal two points of vulnerability contributing to the sex-biased penetrance in neurodevelopmental disorders (NDDs). First, we show that NDD risk genes are biased towards higher expression in females, identifying the NDD gene MEF2C as a critical transcription factor for female-biased expression. Second, we identify a significant contribution of X chromosome genes to NDD pathobiology. We construct a gene regulatory map of X-linked risk genes to enable functional studies of genetic variants that likely disrupt gene expression in the developing brains of autistic males. Together, these results point towards an outsized contribution of the X-chromosome to both the origin of sex differences in the developing human cortex and NDD vulnerability. We propose a model where female-biased vulnerability is driven by coding variation within genes while male-biased vulnerability is driven by noncoding variation in regulatory elements that affect gene expression.

Sex differences↗

PubMed2025

Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.

PURPOSE: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression. METHODS: We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband. RESULTS: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes. CONCLUSION: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.

Humans↗

PubMed2025

KLHL13 functional defects cause neurodevelopmental disorder in humans that can be rescued via inhibition of AURKB in cellular and animal models.

PURPOSE: Neurodevelopmental disorders (NDDs) are characterized by limitations in brain development. This study aims to determine the genetic causes of NDD in humans. METHODS: Exome sequencing was used to detect genetic variants of KLHL13, which encodes Kelch like protein 13 (KLHL13), in four families segregating in an X-linked pattern. In silico protein modeling and overexpression in heterologous cells were used to determine the variant's impact. klhl13 loss of function was modeled in zebrafish, followed by rescue studies using human KLHL13 messenger RNA (mRNA) and an Aurora Kinase B (AURKB) inhibitor. RESULTS: We found one frameshift and three missense hemizygous variants of KLHL13 in individuals exhibiting NDD characteristics, such as intellectual disability (ID) and macrocephaly. Three-dimensional protein modeling simulation predicted the alteration of the KLHL13 protein folding for missense variants. Overexpression of NDD-associated variants in HEK293T cells revealed a significant impact on KLHL13-mediated cell-cycle regulation during mitosis, leading to genomic instability. Knocking down klhl13 in zebrafish resulted in developmental deficits, which were rescued by coinjection of human KLHL13WT messenger RNA but not by transcript encoding NDD variants. Treatment with AURKB selective inhibitor AZD1152-HQPA rescued genomic stability in heterologous cells and neurobehavioral deficits in zebrafish. CONCLUSION: Our results implicate KLHL13-mediated AURKB regulation as a significant contributor to NDD in humans. Inhibiting AURKB activity could serve as a potential therapeutic approach to improve brain development and cognitive function.

Humans↗

PubMed2026

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

BACKGROUND/OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by a complex and multifactorial genetic architecture. In this study, we report a male patient, born to non-consanguineous healthy parents, presenting with ADHD and oppositional defiant disorder (ODD). METHODS: Trio-based whole-exome sequencing (WES) was performed in the proband and both parents. Variant classification was performed according to American College of Medical Genetics and Genomics (ACMG) guidelines, and the potential pathogenicity of the identified variant was further assessed through multiple in silico prediction algorithms and protein structural analyses. RESULTS: WES identified a homozygous variant in the LNX2 gene (NM_153371.4: c.1165G>A, p.Ala389Thr), classified as a variant of uncertain significance (VUS) and supported by multiple in silico predictions. LNX2 is expressed during brain development and encodes an E3 ubiquitin ligase involved in neuronal differentiation and synaptic function. The identified variant is located within the PDZ2 domain, a functionally relevant region involved in protein-protein interactions. Although the variant is reported in population databases (gnomAD ID: rs148429804), it has not been associated with any clinical phenotype, and its presence in the homozygous state has been reported only once, remaining extremely rare and lacking clinical annotation. Structural modelling predicted localized rearrangement of the hydrogen-bonding network within the PDZ2 domain without major conformational changes. Integrative transcriptomic, and single-cell analyses further supported the biological relevance of LNX2 in neurodevelopment, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs. CONCLUSION: Although the identified LNX2 variant cannot be considered causative for the patient's phenotype and a definitive disease-gene relationship cannot be established based on a single individual, the complementary genetic, structural, and transcriptomic findings support the biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders. Additional independent patients and functional studies will be required to clarify its contribution to human disease.

Child↗

PubMed2026

Development of a human iPSC and patient phenotyping resource for preclinical investigations of neurodevelopmental disorders.

In this manuscript, we report the development of a comprehensive resource designed to harness the transformative potential of patient-derived induced pluripotent stem cells (iPSCs) to advance the study of neurodevelopmental disorders (NDDs). Using CRISPR-Cas-mediated genome editing, the Human Neuron Core generated a repository comprising 29 isogenic iPSC pairs, two sex-matched parental control iPSC pairs, and one unmatched patient line representing six monogenic NDDs: Tuberous Sclerosis Complex, PTEN Hamartoma Tumor Syndrome, KCNQ2 Developmental and Epileptic Encephalopathy, FOXG1 Syndrome, Phelan-McDermid Syndrome, and SETBP1 Haploinsufficiency Disorder. In parallel, detailed clinical phenotyping data were collected to enable comparison of cellular phenotypes with clinical severity in future studies. This integrated collection of genetically defined iPSC lines and associated clinical data provides a powerful platform for investigating disease mechanisms and advancing iPSC-based drug discovery for NDDs.

Humans↗

PubMed2026

Expanding the Clinical Spectrum of DHX30-Related Neurodevelopmental Disorder: A Case Report and a Scoping Review.

BACKGROUND: Whole exome sequencing (WES) has improved diagnostic rates for neurodevelopmental disorders (NDDs) while introducing challenges in novel variant interpretation. DHX30-related NDD (DHX30-NDD) is a recently described condition with an evolving phenotypic spectrum. OBJECTIVES: To expand the understanding of the DHX30-NDD genotype-phenotype spectrum by integrating a case-based WES interpretation with a scoping review. METHODS: We performed comprehensive genetic analysis (karyotyping, microarray, WES) on a proband with global developmental delay (GDD). A systematic literature search of PubMed/MEDLINE, Scopus and Google Scholar from database inception to April 2026 identified 10 publications including 51 individuals with DHX30-NDD. Clinical and genetic data were extracted to characterize the genotype-phenotype spectrum. RESULTS: The proband presented with GDD and right microtia, harbouring a de novo heterozygous pathogenic DHX30 missense variant (c.1478G > A; p.Arg493His), confirming DHX30-NDD. To our knowledge, this is the first reported individual with DHX30-NDD and microtia. The scoping review confirmed DHX30 variants are formed predominantly de novo and affected both sexes (22 males; 29 females). Hallmark manifestations were motor delay (50/51; 98.0%), GDD/ID (48/49; 98.0%), hypotonia (48/51; 94.1%), feeding difficulties (38/51; 74.5%), ataxia (17/23; 73.9%), abnormal brain imaging (36/49; 73.5%) and absent expressive language (35/48; 72.9%). Digital anomalies (31/51; 60.8%), eye anomalies (28/51; 54.9%), autistic behaviours (24/44; 54.5%), sleep disturbances (26/51; 51.0%), joint hypermobility (25/51; 49.0%), microcephaly (23/51; 45.1%) and ear anomalies (22/51; 43.1%) were also frequent. CONCLUSIONS: This study potentially expands the phenotypic spectrum of DHX30-NDD, highlights the clinical utility of WES for diagnosing GDD and underscores the importance of ongoing WES reanalysis for evolving variant interpretation.

DHX30↗

PubMed2026

Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).

PURPOSE: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ β-Catenin pathway. In 2021, 11 pediatric patients with monoallelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features-herein referred to as TCF7L2-related neurodevelopmental disorder-is urgently needed. METHODS: We leveraged multiple methods (eg, GeneMatcher, DECIPHER, literature review, and public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n = 11) from more than 60,000 PennMedicine BioBank patients. RESULTS: Among 76 patients with pLOF TCF7L2 variants, speech delay (95.3%), craniofacial dysmorphisms (73.3%), ophthalmologic conditions (65.5%), autism (62.1%), and orthopedic abnormalities (52.6%) were the most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PennMedicine BioBank patients, an association of nominal significance with type 2 diabetes with renal manifestations (odds ratio = 5.8; P = .03) was detected, warranting further investigation. CONCLUSION: This study represents the most comprehensive characterization of TCF7L2-related neurodevelopmental disorder to date, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectra. We opened a Simons Searchlight natural history study that is now available for patient enrollment to enhance the understanding of this condition.

Neurodevelopmental syndrome↗

PubMed2026

Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis-version 1.

OBJECTIVE: To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs). METHODS: Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis. INFORMATION SOURCES: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95% CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available. RESULTS: We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as 'Norway 1' and 'Norway 2' for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%). CONCLUSIONS: In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.

Humans↗

PubMed2024

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease. METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. CONCLUSION: Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder.

Humans↗

PubMed2025

Different mutations in TBL1XR1 lead to diverse phenotypes of neurodevelopmental disorder: two case reports.

The TBL1XR1 gene (Transducin beta-like 1X-linked receptor 1) is responsible for encoding the TBL1XR1 protein, an important component of the NCoR and SMRT corepressor complexes. 48 missense variants of the TBL1XR1 gene have been reported, which are associated with various phenotypes of neurodevelopmental disorders, including West syndrome, Pierpont syndrome, and others. However, given the important role of TBL1XR1 in neurological diseases, it is still necessary to further explore the variation of TBL1XR1. In this study, we present two patients with distinct variants and phenotypes. Patient 1 exhibits global developmental delay, intellectual disability, delayed language development, and seizures. While patient 2 displays mild facial dysmorphism, significant developmental delay, feeding difficulties, and increased muscle tone. Through trio whole-exome sequencing, two novel pathogenic variants in the TBL1XR1 gene were identified: A heterozygous NM_024665.6:c.940G > T (p.Val314Phe) variant in patient 1 and a heterozygous NM_024665.6:c.1387G > T (p.Asp463Tyr) in patient 2. Discovery of these two novel variant sites expands the mutation spectrum associated with the TBL1XR1 gene.

Child↗

PubMed2025

CLINICAL AND COGNITIVE PHENOTYPING OF COPY NUMBER VARIANTS ASSOCIATED WITH NEURODEVELOPMENTAL DISORDERS FROM A MULTI-ANCESTRY BIOBANK.

Clinical biobanks with electronic health records (EHRs) linked to genotype data continue to expand yielding an opportunity to further characterize disease-relevant genomic risk factors, yet few recall-by-genotype studies from biobanks have been published to date. For example, copy number variants (CNVs) that significantly increase risk for multiple neurodevelopmental disorders (NDDs) and negatively affect neurocognition, may present in up to 2% of population cohorts, with public health implications for ascertaining NDD CNV carriers. From BioMe, a multi-ancestry biobank derived from the Mount Sinai healthcare system (New York, NY), 892 adult participants were recontacted for deep phenotyping, including 335 NDD CNV carriers as well as comparators, 217 individuals with schizophrenia and 340 controls. Clinical and cognitive assessments were administered to each participant. There was no disclosure of genetic information. Eight percent of recontacted biobank participants completed the study (30 NDD CNV carriers across 15 unique loci, 20 schizophrenia and 23 controls). The study sample had a mean age of 48.8 (10.2) years, was 66% female and of diverse ancestry, 36% African, 34% Hispanic, and 26% European. Overall, 70% of 30 NDD-CNV carriers harbored at least one neuropsychiatric or developmental phenotype, including 40% with mood or anxiety disorders. Further, 22 NDD CNV carriers were significantly impaired compared to controls on digit span backwards (Beta=-1.76, FDR=0.04) and digit span sequencing (Beta=-2.01, FDR=0.04), but higher performing than schizophrenia on verbal learning (Beta=4.5, FDR=0.05). Thirty NDD CNV carriers were successfully recruited from a multi-ancestry biobank, as well as healthy controls and low-functioning individuals with schizophrenia. Deep phenotyping corroborated past reports, while also identifying discordance with EHRs. Future recall-by-genotype studies may further benchmark the study design and elucidate feasibility.

Biobank↗

PubMed2026

Generation of a hiPSC from a patient with an ITSN1-associated neurodevelopmental disorder spectrum carrying biallelic c.2893_2894insA (p.Tyr965Ter) genetic variant.

De novo truncating variants in ITSN1 are implicated in neurodevelopment disorders spectrum, however, biallelic variants in ITSN1 have not been previously identified. Here we present a hiPSC line generated from a patient dermal fibroblast carrying biallelic variant, c.2893_2894insA (p.Tyr965Ter). The hiPSC line expresses core stemness markers, mycoplasma free with normal karyotype and demonstrate trilineage differentiation capacity. The hiPSC line provides a valuable in-vitro model system to investigate its role in early brain development and neurodevelopmental disorders.

Humans↗

PubMed2025

Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.

PURPOSE: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle, a key regulator of intracellular redox homeostasis. Recently, 5 patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy. METHODS: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical, and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency. RESULTS: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed 2 severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation. CONCLUSION: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of developmental epileptic encephalopathy, and propose novel biomarkers for diagnosis and treatment.

Humans↗

PubMed2026

35 Individuals With HUWE1-Related Neurodevelopmental Disorder and Suggested Clinical Evaluations.

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well as additional multisystemic findings. Intrauterine growth restriction (IUGR) and feeding difficulties were common in the neonatal period. It is notable that nearly all females had de novo variants, and males had de novo or inherited variants from clinically unaffected carrier mothers. Three genetic hotspots were identified in evolutionarily conserved regions of HUWE1 that have clinical impact. This report provides additional characterization of the spectrum of HUWE1-related neurodevelopmental disorder (HNDD).

Humans↗

PubMed2024

Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.

PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.

Humans↗

PubMed2026

Multiomic approaches identify a rare CCG repeat expansion in BCLAF3 in neurodevelopmental disorders.

BACKGROUND: Tandem repeat expansions have been implicated in various neurological conditions. Here, we present a novel hypermethylated CCG repeat expansion on Xp22 in the 5'UTR of BCLAF3 in males with neurodevelopmental disorders. METHODS: We used patient-derived fibroblasts and neuronal models from a family with BCLAF3 repeat expansions to generate multiomic data and investigate downstream molecular consequences of the repeat expansion. To identify additional affected individuals with BCLAF3 repeat expansions, we screened methylation arrays (n = 12,375) and short-read genomes (n = 15,963) from probands with neurodevelopmental presentations. We also characterized BCLAF3 repeat expansions in the general population using long-read sequencing data (n = 793) and population-level short-read sequencing data (n = 410,076). RESULTS: Long-read sequencing validated hypermethylation of expanded repeats. Patient-derived cells showed repressed BCLAF3 RNA and protein expression. We show that the BCLAF3 CCG repeat expansion constitutes a previously uncharacterized fragile site (FRAXG) that shifts the surrounding chromatin compartment from open euchromatin to closed heterochromatin. Using our multiomic screening approaches, we identified three additional unrelated males and one related male cousin with long-read sequencing validated (n = 2) or short-read sequencing predicted (n = 2) repeat expansions. In one family, the BCLAF3 repeats segregate with more severe phenotypes than expected for the primary diagnoses. Long-read sequencing in three carrier mothers showed skewed X-inactivation against the repeat expansion, highlighting the potential deleterious effect of an allele with an expansion. Expansions were absent in long-read sequencing data from control populations. Assessment of the BCLAF3 repeat expansion in the UK Biobank indicates that it may be ~ 20X rarer than FMR1 repeat expansions. CONCLUSIONS: CCG repeat expansions in the 5'UTR of BCLAF3 likely constitute a novel genetic etiology associated with X-linked neurodevelopmental phenotypes in males. Future work will be essential to delineate the phenotypic spectrum and determine a disease pathomechanism.

BCLAF3↗