Background Disrupted RNA processing is increasingly recognized as a key driver of severe neurodevelopmental disorders. Variants in the Integrator catalytic subunit INTS11 and its binding partner BRAT1 lead to clinically overlapping phenotypes, yet only the molecular function of INTS11 has been relatively well characterized. In contrast, the mechanistic contribution of BRAT1 to RNA metabolism and disease has remained unclear, leaving major gaps in variant interpretation and diagnostic classification.Methods We employed an integrated genetic, molecular, and in vivo approach to investigate the impact of INTS11 and BRAT1 mutations on U small nuclear RNA (U snRNA) processing. Patient-derived fibroblasts and lymphoblastoid cells were analysed by western blotting, RT-qPCR and fluorescence in situ hybridization to assess U1 snRNA 3 '-end processing and nuclear retention. To validate the functional consequences of Integrator deficiency in vivo, we generated and characterized an ints11 knockout zebrafish model.Results We identified novel biallelic variants in INTS11 and BRAT1 in individuals with overlapping neurodevelopmental features. While defective snRNA processing is anticipated in INTS11 deficiency, this study provides the first direct demonstration of impaired U1 snRNA processing across multiple INTS11-mutated patient cells. Critically, we show that BRAT1 mutations also compromise U1 snRNA 3 '-end processing, leading to nuclear accumulation of unprocessed transcripts. These findings provide direct evidence of BRAT1's role in RNA processing and establish Integrator dysfunction as a primary pathogenic mechanism in BRAT1-associated neurological disease. The magnitude of U1 snRNA misprocessing closely correlates with clinical severity across the BRAT1 cohort, highlighting its potential as a diagnostic biomarker. Consistently, the ints11 knockout zebrafish model recapitulates core patient features - including microcephaly, neurodevelopmental defects, and U snRNA processing defects - further validating the causal role of Integrator deficiency in vivo.Conclusions Our results redefine BRAT1-associated neurological disorders as Integrator-related diseases driven by RNA processing defects. Nuclear accumulation of unprocessed U1 snRNAs emerges as a robust biomarker for variant interpretation, disease severity, and patient stratification, particularly in BRAT1 cases. These findings broaden the clinical and molecular spectrum of Integrator dysfunction and provide a foundation for improved diagnostic and translational approaches.

Background and ObjectivesDevelopmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort.MethodsWe retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up.ResultsPathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype.DiscussionThis large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.

DENND2B is a DENN (differentially expressed in normal and neoplastic cells) domain-containing protein that has important roles in regulating the cell cycle, cell division and ciliogenesis, but to date has not been associated with any human disease. Here, we report on 11 individuals with monoallelic variants in DENND2B with a shared constellation of features and perform in silico and in vivo zebrafish modelling of the DENND2B variants identified in these patients. Features shared among these patients include developmental delay, intellectual disability and psychiatric/behavioural concerns, and episodes of psychosis and/or catatonia. Additional features common to our cohort include epilepsy, muscle weakness/hypotonia and a wide range of congenital anomalies across different organ systems. Identified patient variants affect well-conserved amino acids and are predicted to be deleterious to DENND2B function by in silico prediction algorithms and structural modelling. Nine of the 10 observed patient variants were modelled in zebrafish and confirmed to result in loss of DENND2B function. Altogether, these findings suggest that monoallelic loss-of-function variants in DENND2B cause a novel autosomal dominant neurodevelopmental disorder with variable vulnerability to psychosis and/or catatonia.

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.

ObjectiveThis study is an example of the contribution of exome sequencing (ES) in selected prenatal indications, while illustrating the complexity of interpreting prenatal genetic testing. Therefore, one of the aims of this study was to better describe antenatal phenotypes.MethodsThis was a multicenter, comparative, prospective study assessing high-throughput sequencing performance (targeted gene panel versus exome sequencing) in selected prenatal indications.ResultsTrio-ES was performed on 86 fetuses, allowed making a definite etiological diagnosis in 28% of cases (24/86). One-third of diagnoses were obtained only after exome analysis (8/24, 33%). The diagnostic yield varied according to the indication and was the highest for vermian hypoplasia (5/12, 42%) and polymalformative syndromes (30%, 8/27) indications. The variants identified were mainly missense variants in ciliopathy (18%, 6/33) and cytoskeleton (15%, 5/33) genes. Among the etiological diagnoses, one fetus carried a postzygotic mosaic variant in RHOA.ConclusionIn selected indications, the diagnostic yield of ES was close to 30% and varied according to the indications, showing the importance of clearly define the malformations justifying this approach. An etiological diagnosis was made in 23 families, within a timeframe compatible with pregnancy, thus improving the management of the pregnancy and/or the unborn child.

Abstract Background NPTN encodes human neuroplastin (hNp), a transmembrane immunoglobulin (Ig)-superfamily glycoprotein and a subunit of the plasma membrane calcium (Ca2+)-ATPases (PMCA). The critical importance of hNp and its associations with PMCA in the human brain remains unknown. Methods Here, we describe de novo NPTN variants in individuals with autism and mild-to-severe DD/ID and evaluate their effects using animal models and in silico, molecular, and cellular approaches. Results Four individuals present variants affecting the two hNp isoforms, hNp55 and hNp65. Other four variants affect only the hNp65 isoform. Two individuals independently carry the same loss-of-function nonsense variant, predicted to cause haploinsufficient production of all hNp isoforms. Haploinsufficient Nptn +/– mice displayed reduced levels of Np and PMCA and exhibited altered social behavior. Insufficient Np55/65 production in neurons resulted in reduced PMCA expression and function. Two missense variants caused particular structural and thermodynamic abnormalities and lower expression of hNps in human embryonic kidney (HEK) cells. In primary neurons, these hNp variants failed to regulate cytosolic Ca2⁺ transients. In Drosophila, a missense mutation affecting the PMCA interaction failed to prevent the lethal phenotype caused by hNp ortholog elimination. Conclusions We show that a novel neurodevelopmental disorder characterized by intellectual disability and autism originates from haploinsufficient NPTN gene dosage or insufficient functionality of mutant hNp related to PMCA hypofunction.

Genetic disorders affecting the epigenetic machinery constitute a major group of neurodevelopmental conditions. Pathogenic variants in several ARID transcription factors—particularly ARID1A , ARID1B , and ARID2 —cause Coffin–Siris syndromes, all characterized by intellectual disability (ID). These genes encode core subunits of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex. In contrast, ARID family members that function in other regulatory complexes have remained largely unexplored in neurodevelopmental disease. Here, we identify 29 individuals carrying heterozygous ARID5B variants, of which 24 (83%) introduce premature termination codons in the exceptionally long final exon, one affects the exon 9 splice donor site, and four are missense variants in conserved domains within the N-terminal half of the protein. Using a CRISPR–Cas9 knock-in mouse model harboring the p.Q522Ter variant, together with in vitro assays, we investigated the functional consequences of C-terminal ARID5B truncations. All affected individuals presented with global developmental delay or ID—most commonly mild—and frequent speech and language impairment. Recurrent features included kidney malformations, behavioral difficulties, and recurrent infections of the respiratory and urinary tracts. Two individuals experienced central nervous system inflammation, and two infants presented with persistent pulmonary hypertension. Remarkably, 19 of 29 variants (66%) cluster within the first quarter of exon 10, are de novo, and escape nonsense-mediated mRNA decay (NMD), which we confirmed for two variants affecting seven individuals. Variants outside this region were inherited. Heterozygous mice exhibited developmental and behavioral abnormalities, while homozygous mutations was perinatally lethal. Truncations and a small deletion within a predicted nuclear localization signal (NLS) caused cytosolic mislocalization of ARID5B, whereas the isolated C-terminal half retained nuclear localization, suggesting an independent distal NLS. Collectively, these findings define ARID5B -related neurodevelopmental disorder as a distinct clinical entity and reveal how disruption of specific ARID5B domains impacts protein localization, mammalian development, immune and neurobehavioral function.

Biallelic loss-of-function variants in FBXO31 cause autosomal-recessive intellectual disability. A recurrent de novo variant, c.1000G>A(p.Asp334Asn), has been described in association with an autosomal-dominant phenotype. To refine this phenotype and its clinical implications, we re-evaluated three published cases and ascertained four additional probands via advocacy networks, GeneMatcher, and clinician referral. Phenotyping included neurologic, behavioral, and dysmorphology assessment. All seven individuals carried the recurrent de novo FBXO31 p.Asp334Asn variant. A core neurodevelopmental profile was observed and included cerebral palsy (mixed hypotonia, spasticity, and dystonia), global developmental delay/intellectual disability, and speech impairment. Neuropsychiatric features were sometimes prominent and included attention-deficit/hyperactivity disorder, anxiety, stereotypies, autistic features, and behavioral dysregulation. Neuroimaging often showed a hypoplastic corpus callosum and posterior-predominant white-matter changes. In one individual, gray matter heterotopias were also observed. A subtle but consistent facial gestalt was noted. Recurrent FBXO31 p.Asp334Asn variants lead to a recognizable neurodevelopmental syndrome. Based on our findings, we recommend including FBXO31 in diagnostic algorithms for cerebral palsy and neurodevelopmental disorders. We propose the descriptive term "autosomal dominant FBXO31-associated neurodevelopmental disorder," and-consistent with the validating laboratory and with support from the FBXO31 Foundation-propose the eponym "Kruer syndrome."

BACKGROUND AND OBJECTIVES:Developmental and epileptic encephalopathies (DEEs) with early burst-suppression EEG (EIDEE-BS) are among the most severe neonatal epileptic syndromes, typically presenting in the first months of life with refractory seizures and profound neurodevelopmental impairment. Although variants in the KCNQ2, STXBP1, and SCN2A genes are recognized as major causes, the full genetic spectrum remains uncertain. We aimed to delineate the electroclinical characteristics, genetic etiologies, and long-term outcomes in a large MRI-negative EIDEE-BS cohort. METHODS:We retrospectively analyzed 110 patients with BS EEG enrolled from a database of 1,540 individuals with suspected genetic epilepsies (2008-2023). Clinical, EEG, and genetic data were systematically collected. Patients were stratified into 4 groups: KCNQ2, STXBP1, "other pathogenic variants," and "without a genetic diagnosis." EEG traces were reviewed independently, and outcomes were assessed through long-term follow-up. RESULTS:Pathogenic or likely pathogenic variants were identified in 62.7% of patients and involved 23 genes, including 2 copy number variants. KCNQ2 (n = 24) and STXBP1 (n = 16) accounted for one-third of diagnoses, whereas SCN2A (n = 3) and KCNT1 (n = 2) were less frequent. In KCNQ2 cases, seizures and BS onset occurred earlier than in STXBP1 cases: mean 2 days vs 6 weeks for seizures and 3 days vs 2 months for BS, respectively. A typical BS pattern (bursts longer than suppressions) strongly correlated with KCNQ2 and STXBP1 variants. Novel associations were found with DPM1, GRIN2A, KCNT2, PIGO, PURA, WWOX, and candidate genes (KMT2E, SNAP25, and SYT1). Most variants were de novo heterozygous; however, recessive and X-linked inheritance patterns were also observed. Mortality was high (25%), primarily from status epilepticus and complications of severe disability. Most patients (72.5%) had persistent seizures at follow-up (a mean of 6.5 years), as well as profound intellectual disabilities, irrespective of genotype. DISCUSSION:This large series highlights the strong monogenic basis of EIDEE-BS. KCNQ2, STXBP1, and SCN2A were the most commonly affected genes. Early EEG features, particularly BS timing and morphology, can help anticipate the underlying genotype and guide precision therapy, including the early use of sodium channel blockers in selected cases. These findings support recent ILAE reclassification efforts and underscore the importance of comprehensive genomic testing for improved diagnosis and counseling.

BACKGROUND:NKX2-1-related disorders result from heterozygous variants in NKX2-1, a gene crucial for brain, lung, and thyroid development. Although movement disorders, hypothyroidism, and neonatal respiratory distress are recognized, the full phenotype and genotype-phenotype relationships remain incompletely defined. OBJECTIVES:To delineate neurological, respiratory, and endocrine features across ages, characterize movement disorder trajectories - particularly chorea - and explore genotype-phenotype associations with clinical relevance. METHODS:We conducted a multicenter, cross-sectional study recruiting participants through referral clinicians and European networks. Standardized clinical and genetic data were captured in an electronic database and analyzed with descriptive and inferential statistics. RESULTS:Sixty-eight individuals (37 female; median age 16 years, range 2-60 years) were included. Motor delay was the commonest presenting feature (~60%); neonatal respiratory distress syndrome occurred in one-third of cases. The brain-lung-thyroid triad was present in almost half. Chorea affected over 90% and began in early childhood; it was more frequent with single nucleotide variants than with deletions. Deletions are associated with better gross motor function. Frameshift or nonsense variants showed greater respiratory involvement, and variants in the exon-3 homeobox region were associated with age-related reduction of chorea. Neonatal respiratory distress predicted later respiratory symptoms. Greater abnormal involuntary movement severity correlated with poorer manual and gross motor function. Hypotonia and untreated hypothyroidism are associated with more severe chorea. Psychiatric comorbidity occurred in over one-third of cases, mainly attention-deficit/hyperactivity symptoms. CONCLUSIONS:This largest cohort to date shows early neurological onset, genotype-specific outcomes, and frequent psychiatric comorbidity in NKX2-1-related disorders, refining clinical expectations and supporting genotype-informed diagnosis, counseling, and management. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Context Hyperphagia, overweight, and obesity are frequent in people with rare neurodevelopmental disorders (NDDs). Prader-Willi syndrome (PWS) is a rare NDD with hyperphagia and hyperghrelinemia. Objectives To measure ghrelin levels, hyperphagia and caregiver burden in rare NDDs patients to understand pathophysiology and improve care. Design A single-visit, noninterventional, national, multicenter, cross-sectional study. Setting Seven French reference centers for rare NDDs participated. Patients A total of 130 patients (43% children) with a rare genetic NDD (27 distinct conditions) were included. Their median age was 19.8 years. Three control groups were used for comparison: "PWS" (n = 153), "Obese" (n = 49), and "Lean" (n = 31) groups. Main outcome measure(s) The primary endpoint was ghrelin level (total, acylated, unacylated). The first secondary endpoint was hyperphagia questionnaire (HQ) scores. Results Median total ghrelin levels were 76.7 (22.2-1110.9) pg/mL; median acylated levels were 33.7 (8.0-754.3) pg/mL; and median unacylated levels were 44.2 (11.5-356.6) pg/mL, which were lower than the PWS group (P < .001) and no different from the Obese group. The mean HQ total score was 26.3 (10-46) for children and 24.0 (11-52) for adults. The HQ total score was statistically higher in children with NDDs and lower in adults compared to PWS. The mean Zarit Burden Interview score was 37.8 (6-74) in children and 37.6 (2-76) in adults, and was positively correlated with the HQ total score. Conclusion Ghrelin levels were normal in our study population. Hyperghrelinemia is a biomarker of PWS. Hyperphagia is more prevalent and severe in children with NDDs compared with PWS.

Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated.To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations.By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays.This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia. Using whole-genome sequencing and proteomics, Zech et al. have shown that many patients with suspected monogenic dystonia carry mutations that are undetectable with exome analysis alone. Complementary approaches, such as RNA sequencing and functional studies, can improve rates of diagnosis.

The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.

The orphan nuclear hormone receptor estrogen-related receptor γ (ESRRG, also known as ERRγ) functions as an inducible transcription factor, regulating the expression of endocrine and metabolic genes. Among its ESRR paralogs, ESRRG exhibits the highest mutational constraint, yet it remains unlinked to a defined disease phenotype. We clinically describe eight individuals from seven unrelated families having heterozygous, mostly de novo variants in ESRRG: c.410G>A (p.Gly137Glu), c.446A>G (p.Lys149Arg), c.539G>A (p.Cys180Tyr), c.550C>T (p.Arg184Cys), c.1346T>G (p.Leu449Arg), and c.1352dup (p.Leu451Phefs∗38). Cell proliferation and ERR response element (ERRE) reporter gene expression have been examined in transient transfected ESRRG-knockout HEK293T cells for each variant compared to wild-type ESRRG. Immunofluorescence was performed to inspect the protein’s subcellular localization. All identified variants are absent in gnomAD (v.4.1), are in silico deleterious, and are located in intolerant segments of the protein. All individuals have motor developmental delay, muscular hypotonia, and eye movement disorders, as well as congenital ataxia or gait imbalance. Other symptoms include joint hyperflexibility, dysarthria, myopia, and growth delay. Molecular modeling of the identified variants suggests a reduction in protein function. ESRRG knockout resulted in a significantly increased proliferation rate in ESRRG-knockout HEK293T cells. Overexpression of wild-type ESRRG restored cell proliferation, while overexpression of the identified variants did not. Despite the correct nuclear localization of all identified variants, the reporter gene assay revealed a significant reduction in transcriptional activity for all identified variants. Given the acquired clinical, molecular, and functional data, we implicate ESRRG in the etiology of a non-progressive congenital movement disorder with ataxia.

BACKGROUND:Tubulinopathies are neurodevelopmental disorders caused by pathogenic variants in tubulin-encoding genes, typically presenting with intellectual disability (ID), epilepsy, motor impairments, and distinct brain malformations. While most cases are de novo and severe, recent reports suggest the existence of milder imaging and clinical phenotypes, including familial cases with attenuated symptoms. METHODS:Through international collaboration, clinical, imaging, and molecular data were collected from 24 individuals (≥4 years old) across 16 families with pathogenic or likely pathogenic variants in TUBA1A, TUBB2B, TUBB3, TUBB, or TUBB2A. Patients were selected based on absence of ID and availability of brain MRI. Genetic inheritance patterns and genotype-phenotype correlations were analyzed. RESULTS:Fifteen patients were identified through fetal or pediatric imaging and nine through familial investigations. No cases exhibited severe cortical gyration anomalies. TUBB3 was the most frequently mutated gene (12/24, 50%), and 7 out of 14 total variants were inherited. Two recurrent variants, TUBB3 p.(Pro357Leu) and TUBB p.(Asn52Ser), were associated with non-ID phenotypes in both the current cohort and literature. CONCLUSIONS:This study broadens the spectrum of tubulinopathies to include mild imaging phenotypes with attenuated clinical features in children and adults. Absence of major cortical malformations, inherited mutations, and specific genetic variants may serve as favorable prognostic markers. These findings have important implications for genetic counseling, particularly in prenatal cases.

BackgroundAarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in theFGD1gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.MethodsPhenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants inFGD1, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.ResultsThis study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.ConclusionA better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation ofFGD1variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients.

INTRODUCTION:Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurological disease usually described in adults. Expanded CAG repeats in the ATXN2 gene can lead to pediatric onset. This study aims to describe the natural history of SCA2 in children. METHODS:We analyzed clinical and genetic data from 22 children with SCA2 across 17 institutions and compared them to 20 previously reported cases. RESULTS:The phenotype of pediatric SCA2 can be divided into two distinct groups based on CAG repeat size and age. In the infantile group (n = 9), developmental delay and seizures were prominent features, along with cerebellar and cerebral atrophy. In the juvenile group (n = 13), the disease was a cerebellar degeneration similar to adults. A threshold of 88 ± 4 CAG repeats distinguished the infantile group from the juvenile group. Pediatric SCA2 type was independent of parental origin; SCA2 was maternally inherited in 22%, including three infantile presentations. DISCUSSION:This large cohort of pediatric SCA2 disease provides the first comprehensive description of its characteristics, which differ from those of SCA7. Indeed, the phenotypic spectrum of SCA7 in children is continuous, while that of SCA2 is bimodal. Although pediatric SCA2 can be difficult to diagnose by genome-wide sequencing, it is a recognizable disease that can be easily diagnosed with a targeted study of the number of CAGs in ATXN2. Genetic counseling for families should consider the significant proportion of maternal transmission.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and “specificity residues” impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.