Focus Area Tag: Neurogenomics

Am J Hum Genet. 2025 Sep 3:S0002-9297(25)00320-9. doi: 10.1016/j.ajhg.2025.08.010. Online ahead of print. ABSTRACT Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity. PMID:40925378 | DOI:10.1016/j.ajhg.2025.08.010

Nat Med. 2026 Jul 21. doi: 10.1038/s41591-026-04527-y. Online ahead of print. ABSTRACT SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient’s phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 . PMID:42481851 | DOI:10.1038/s41591-026-04527-y

Front Neurol. 2026 Jul 16;17:1793300. doi: 10.3389/fneur.2026.1793300. eCollection 2026. ABSTRACT BH4 deficiencies may occur with or without hyperphenylalaninemia (HPA). If identified early through neonatal screening for PKU, the clinical follow-up aims to prevent the onset of typical disease symptoms. In contrast, for the conditions not associated with HPA, diagnosis usually occurs once symptoms manifest, and follow-up focuses on monitoring the treatment’s effectiveness in restoring normal neurological function. Except for pterin-4-alpha-carbinolamine dehydratase defect (PCCDd), the core symptoms and natural course of these diseases involve neurodevelopmental impairment and movement disorders. Current information on clinical follow-up and outcome comes from retrospective observational studies, with standardized measures used in only a few of them. Serial clinical observations focusing on the two most consistent areas of neurological impairment are the best predictors of outcome and the main follow-up targets. Available clinical data, often aggregating early- and late-treated patients, show that the best clinical outcome occurs in autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (AD-GTPCHd). In contrast, for recessive conditions, prognosis is variably associated with both the timing of treatment (autosomal recessive [AR]-GTPCHd, 6-pyruvoyltetrahydropterin synthase [PTPS]d, sepiapterin [SR]d, q-dihydropyridine reductase [DHPR]d) and the severity of metabolic derangement (AR-GTPCHd, PTPSd). Neurocognitive, psychiatric, and sleep disorders are currently underestimated and can occur in children and adults, affecting social adaptation and quality of life. Among metabolic alterations, blood Phe levels, when altered, warrant regular monitoring. CSF evaluation can be considered in subjects unresponsive to treatment or with an unexpected clinical course. CSF 5-MTHF monitoring should be reserved for patients with DHPRd experiencing neurological deterioration and seizures. Monitoring prolactin levels, when altered, may assist in personalizing pharmacological treatment. Serum magnesium and glucose are metabolic markers that should be assessed in PDCCd. Brain MRI monitoring is recommended for patients experiencing unusual courses, epilepsy, and neurological deterioration (particularly in PTPSd and DHPRd). A DAT scan is advised for those with AD-GTPCH who present or develop Parkinsonism, and EEG monitoring should be conducted for every patient with epilepsy or suspected seizures. For future clinical studies, it is mandatory that the clinical assessment adopt standardized tools that score impairment across neurological and behavioral domains, taking the patient’s age into account. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=1144143, identifier (CRD420251144143). PMID:42534655 | PMC:PMC13422167 | DOI:10.3389/fneur.2026.1793300

Nat Commun. 2026 May 30. doi: 10.1038/s41467-026-73455-9. Online ahead of print. ABSTRACT Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential. PMID:42218136 | DOI:10.1038/s41467-026-73455-9

Parkinsonism Relat Disord. 2026 May 22;148:108367. doi: 10.1016/j.parkreldis.2026.108367. Online ahead of print. ABSTRACT BACKGROUND: While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial. OBJECTIVES: Establish a list of genetic movement disorders considered essential as determined by a group of MD experts. METHODS: All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic. RESULTS: Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington’s disease, PxMD-PPRT2, Wilson’s disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C. CONCLUSION: This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts. PMID:42202611 | DOI:10.1016/j.parkreldis.2026.108367

Cell Genom. 2026 Mar 9:101186. doi: 10.1016/j.xgen.2026.101186. Online ahead of print. ABSTRACT Long-read whole-genome sequencing (LR-WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR-WGS on 267 individuals from 63 autism spectrum disorder (ASD) families and generated an integrated call set combining long- and short-read data. LR-WGS increased detection of gene-disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication-deletion events. By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes and demonstrated the effect of intermediate TR expansions (35-54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% confidence interval [CI], 2.7%-17%) of the heritability of ASD. These findings demonstrate how LR-WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay. PMID:41806827 | DOI:10.1016/j.xgen.2026.101186

Nature. 2026 Apr 8. doi: 10.1038/s41586-026-10334-9. Online ahead of print. ABSTRACT Recently, de novo variants in an 18-nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder that is predicted to affect tens of thousands of individuals worldwide^1,2. RNU4-2 is a non-protein-coding gene that is transcribed into the U4 small nuclear RNA component of the major spliceosome³. ReNU syndrome variants disrupt spliceosome function and alter 5′ splice site selection^1,4. Here we performed saturation genome editing (SGE) of RNU4-2 to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants’ effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across RNU4-2, providing critical insights for both diagnosis and therapeutic development. PMID:41951737 | DOI:10.1038/s41586-026-10334-9

Exp Mol Med. 2026 Apr 8. doi: 10.1038/s12276-024-01331-x. Online ahead of print. ABSTRACT Brain somatic mosaicism (BSM) refers to genome variation within brain cells that results from accumulated postzygotic mutations. These mutations can be used to understand cell lineage, molecular dynamics and disease processes. Unlike most other organs, brain cells are mostly fixed in position and not replaced throughout life. Thus, assessing mosaic variants (MVs) within the brain, including their spread and cell type-specific distributions and correlations with aging and cellular health, can reveal insights into neurodevelopmental, neuropsychiatric and neurodegenerative diseases. Extracting genetic material from human surgical brain resections, pregnancy remnants, or postmortem samples can reveal the origins of brain cells and uncover the effects of aging and disease on genomic integrity. Technological advances combining high-read-depth bulk sequencing, isolation of specific brain cell types, and single-cell multiomics can both detect and quantify MVs with good precision and recall. Research exploiting brain MVs is revolutionizing the understanding of the origins, mechanisms and potential treatments for brain conditions. PMID:41951903 | DOI:10.1038/s12276-024-01331-x

Nat Genet. 2026 Mar 30. doi: 10.1038/s41588-026-02547-5. Online ahead of print. ABSTRACT Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome. PMID:41912934 | DOI:10.1038/s41588-026-02547-5

Nature. 2026 Apr 1. doi: 10.1038/s41586-026-10313-0. Online ahead of print. ABSTRACT The neural crest generates a broad spectrum of cell types that migrate across the body plan to populate multiple tissues¹. However, the relationship between lineages of neural crest derivatives remains unclear, and the extent to which neural crest cells delaminated from the neural tube have specified fates remains debated. Here, leveraging CRISPR barcoding in mice and mosaic variant barcode analysis in humans, we demonstrate robust bilateral progenitor clonal spread of neural crest progenitors along the rostrocaudal axis but limited clonal overlap between sensory and sympathetic lineages. Computational modelling of mosaic variants suggests that most neural crest cells show strong fate restriction before delamination. Real-time imaging of quail embryos further shows a fibroblast-growth-factor-dependent rostrocaudal dispersion of neural crest cells across multiple axial levels. These findings support a model in which neural crest fate bias predominantly emerges within the neural tube, with only a minor subset of delaminated progenitors retaining multipotency to generate both sensory and sympathetic derivatives. PMID:41922758 | DOI:10.1038/s41586-026-10313-0