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Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development. Subunits of the Elongator complex have been implicated in several nervous system pathologies. Here, the authors identify ELP2 variants in six patients with neurodevelopmental anomalies and show in mouse models that these variants impact protein stability and the activity of the complex during brain development.

Background SATB2-associated syndrome (SAS) results from various mutations of the SATB2 gene and associates a neurodevelopmental disorder including major speech delay, intellectual disability, and behavioral problems with dental anomalies, sometimes a cleft palate, risk of osteoporosis, and facial dysmorphism. The principal objective of this study was to describe the oral phenotype of young children with SATB2-associated syndrome, especially in terms of orofacial malformation of Robin Sequence (RS) spectrum (bifid uvula, cleft palate, or RS, dental malformation, feeding and communication, with data from a national cohort. The secondary objective was to determine whether feeding and communication disorders were more severe when associated with an orofacial malformation of RS spectrum. Methods We conducted a retrospective cross-sectional study among the largest possible cohort of patients with a mutation of the SATB2 gene in France. A questionnaire completed by the referring physicians and by telephone with parents enabled us to collect the following clinical information: (1) orofacial morphology, feeding difficulties, and pharyngeal functioning from birth to 3 years, (2) communication and language from 0 to 6 years, (3) speech development at the last examination. Results The study included 40 patients. Early and persistent feeding difficulties were found in 55% of the children. Communication was abnormal from the first months of life, with poor babbling in 85% of them. A major language delay was described in all patients; 65% had a vocabulary of 10 words or less. An anomaly of RS spectrum was found in half the cases, and dental malformations were described in 90%. Feeding difficulties and language delay were greater in the group with one or more orofacial malformations than the group with none. Conclusion This study confirmed the severity of oral involvement, affecting feeding and speech simultaneously, in individuals with SAS. It raises the question of why the oral phenotype involving feeding and speech is more severe in the presence of cleft palate or RS. We recommend close monitoring of prelanguage communication in infants with apparently isolated cleft palate or RS and the search for SATB2 impairment when a cleft palate or RS is found, especially in the prenatal period.

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

Post-mortem genetic analyses may help to elucidate the cause of cardiac death. The added value is however unclear when a cardiac disease is already suspected or affirmed. Our aim was to study the feasibility and medical impact of post-mortem genetic analyses in suspected cardiomyopathy. We studied 35 patients with cardiac death and suspected cardiomyopathy based on autopsy or clinical data. After targeted sequencing, we identified 15 causal variants in 15 patients (yield 43%) in sarcomeric ( = 8), desmosomal ( = 3), lamin A/C ( = 3) and transthyretin ( = 1) genes. The results had various impacts on families, i.e. allowed predictive genetic testing in relatives (15 families), planned early therapeutics based on the specific underlying gene (5 families), rectified the suspected cardiomyopathy subtype (2 families), assessed the genetic origin of cardiomyopathy that usually has an acquired cause (1 family), assessed the diagnosis in a patient with uncertain borderline cardiomyopathy (1 family), reassured the siblings because of a mutation (2 families) and allowed prenatal testing (1 family). Our findings suggest that post-mortem molecular testing should be included in the strategy of family care after cardiac death and suspected cardiomyopathy, since genetic findings provide additional information useful for relatives, which are beyond conventional autopsy.

: Adolescents and young adults with Down syndrome (DS) can present a rapid regression with loss of independence and daily skills. Causes of regression are unknown and treatment is most of the time symptomatic. We did a retrospective cohort study of regression cases: patients were born between 1959 and 2000, and were followed from 1984 to now. We found 30 DS patients aged 11 to 30 years old with history of regression. Regression occurred regardless of the cognitive level (severe, moderate, or mild intellectual disability (ID)). Patients presented psychiatric symptoms (catatonia, depression, delusions, stereotypies, etc.), partial or total loss of independence in activities of daily living (dressing, toilet, meals, and continence), language impairment (silence, whispered voice, etc.), and loss of academic skills. All patients experienced severe emotional stress prior to regression, which may be considered the trigger. Partial or total recovery was observed for about 50% of them. In our cohort, girls were more frequently affected than boys (64%). Neurobiological hypotheses are discussed as well as preventative and therapeutic approaches.

ObjectiveWe aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.MethodsWe sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.ResultsWe describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.ConclusionsSYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

IntroductionTonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described.MethodAfter the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.ResultsWe present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype–phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots.ConclusionOverall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Lamb–Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype–phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

Background Intellectual disability (ID) is the leading cause of patient referral to medical genetic departments in French academic hospitals. Whole genome sequencing (WGS) as a first diagnostic approach is expected to achieve a higher diagnostic yield than the French national reference strategies (RefStrategy) (fragile X expansion testing, chromosomal microarray analysis, and 44 ID genes panel), given its broad and more homogeneous coverage, its ability to identify copy number, structural and intergenic/deep intronic events. Methods DEFIDIAG is a national, prospective pilot investigation, carried out in the framework of the French initiative for genomic medicine ( Plan France Médecine Génomique 2025 ), aimed at comparing the diagnostic yield of WGS trio analysis (WGS-trio) (index case, father, mother) with the RefStrategy in real-life conditions of clinical and laboratory workflows. Both strategies were applied in a blinded fashion in 1239 ID probands (50% were already-tested, 50% were never-tested) with no definitive genetic diagnosis. Among them, a subgroup of 187 patients were randomized to undergo WGS-solo (proband only) in addition to WGS-trio and RefStrategy. Results Four hundred forty two likely pathogenic/pathogenic single-nucleotide variants were identified (for 231 genes) as well as 171 variants of uncertain significance warranting clinical or functional reassessment for a potential reclassification (VUS +) (for 142 genes), 79 likely pathogenic/pathogenic copy number variants and 10 likely pathogenic/pathogenic structural variants. The diagnostic yield for likely pathogenic/pathogenic variants increased from 17.3% with the RefStrategy to 41.9% with WGS-trio in the never-tested patient cohort. An increase of 13.9% was observed in all categories by adding the VUS + , thus raising the yield to 56% for WGS-trio. Overall, WGS-solo enabled the identification of likely pathogenic/pathogenic variants in 29.9% of cases (increasing to 41.1% when including VUS +) compared to 21.9% with the RefStrategy. In addition, following recent reports of de novo variants in the non-coding spliceosomal RNU4-2 gene as a common cause of ID, this gene was subsequently analyzed, leading to the identification of pathogenic de novo variants in 7 patients. Conclusions As a first line test for ID diagnosis, WGS (including for solo situations) proved to be more effective than the reference strategy, in the context of real-life hospital settings in France. Trial registration Prospectively registered with ClinicalTrials.gov under the identifier NCT04154891 (07/11/2019).

Objective: Wolfram syndrome (WS, MIM 222300) is a rare autosomal, recessive neurodegenerative disorder associated with mutations in WFS1, a gene that has been associated with bipolar disorder (BD). WS, characterized by the association of juvenile-onset diabetes mellitus (DM) and bilateral progressive optic atrophy (BPOA), encompasses several other clinical features, including cognitive impairments and psychiatric disorders. Detailed data on the psychiatric phenotype are still scarce, and how WS relates to BD is still unknown. Method: A 17-year-old girl with WS was hospitalized for early-onset BD. A multidisciplinary and developmental assessment was carried out to control mood symptoms and address how BD could be related to WS. Results: Besides DM and BPOA, the patient had several risk factors for BD/mood disorders as follows: (1) a history of abuse and maltreatment; (2) a history of specific language disorder and borderline intelligence associated with academic failure; and (3) a comorbid hypothyroidism. Treatment encompassed all aspects of the adolescent's conditions, such as the use of mood stabilizers, addressing psychosocial and scholastic problems, and treating hypothyroid dysfunction. Conclusion: Given the complexity of WS, this case suggests that the possible association between WS and BD should not only be merely limited to a possible statistical association with WFS1 polymorphism but also to developmental, cognitive, and endocrine risk factors for BD.