Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.

Confirmation of mutations in PROSC as a novel cause of vitamin B 6 -dependent epilepsy.

Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPL or ALDH4A1). In neonatal seizures, defects in ALDH7A1 and PNPO explain a major fraction of cases. Very recently biallelic mutations in PROSC were shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B6 plasma profiles on pyridoxine did not enable the differentiation of patients with PROSC mutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients with PROSC mutations was indistinguishable from ALDH7A1 and PNPO deficiency. We therefore confirm PROSC as a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6 profile under pyridoxine treatment.

The value of plasma vitamin B6 profiles in early onset epileptic encephalopathies.

BACKGROUND: Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. This has so far been investigated in only a small number of patients. METHODS: We evaluated the vitamin B6 vitamers pyridoxal 5'-phosphate (PLP), pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN) and the catabolite pyridoxic acid (PA) in the so far largest patient cohort: reference (n = 50); pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency (n = 6); antiquitin (ATQ) deficiency (n = 21); tissue non-specific alkaline phosphatase (TNSALP) deficiency (n = 2) and epileptic encephalopathy (EE) of unknown etiology tested negative for ATQ and PNPO deficiency (n = 64). RESULTS: High plasma PM concentration was found in all patients with PNPO deficiency irrespective of vitamin B6 supplementation. Their PM concentration and the PM/PA ratio was significantly higher (p < 0.0001), compared to any other patients analysed. One patient with TNSALP deficiency and sampling prior to PN supplementation had markedly elevated plasma PLP concentration. On PN supplementation, patients with TNSALP deficiency, ATQ deficiency and patients of the EE cohort had similar plasma vitamin B6 profiles that merely reflect the intake of supra-physiological doses of vitamin B6. The interval of sampling to the last PN intake strongly affected the plasma concentrations of PN, PL and PA. CONCLUSIONS: PM concentrations and the PM/PA ratio clearly separated PNPO-deficient patients from the other cohorts. The plasma PM/PA ratio thus represents a robust biomarker for the selective screening of PNPO deficiency.

Infectious and immunologic phenotype of MECP2 duplication syndrome.

MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG.

Infantile epileptic encephalopathy, transient choreoathetotic movements, and hypersomnia due to a De Novo missense mutation in the SCN2A gene.

Mutations of the SCN2A gene have originally been described in association with benign familial neonatal-infantile seizures (BFNIS). Recently, single patients with more severe phenotypes and persisting epileptic encephalopathies have been recognized. We report the case of a girl with severe infantile onset epileptic encephalopathy and a de novo missense mutation in the SCN2A gene (c.4025T > C/ = ; p.L1342P/ = ), who presented with a transient choreatic movement disorder, hypersomnia, and progressive brain atrophy. Whole exome sequencing did not reveal any other disease causing mutation. Our patient contributes to the expanding phenotypic spectrum of SCN2A-related disorders and underlines the importance of genetic workup in epileptic encephalopathies.

Autistic Behavior as Novel Clinical Finding in OFD1 Syndrome.

Orofaciodigital syndrome I (OFD1-MIM #311200) is a rare ciliopathy characterized by facial dysmorphism, oral cavity, digit, and brain malformations, and cognitive deficits. OFD1 syndrome is an X-linked dominant disorder reported mostly in females. The gene responsible for this condition, OFD1 centriole and centriolar satellite protein (OFD1), is involved in primary cilia formation and several cilia-independent biological processes. The functional and structural integrity of the cilia impacts critical brain development processes, explaining the broad range of neurodevelopmental anomalies in ciliopathy patients. As several psychiatric conditions, such as autism spectrum disorders (ASD) and schizophrenia, are neurodevelopmental in nature, their connections with cilia roles are worth exploring. Moreover, several cilia genes have been associated with behavioral disorders, such as autism. We report on a three-year-old girl with a complex phenotype that includes oral malformations, severe speech delay, dysmorphic features, developmental delay, autism, and bilateral periventricular nodular heterotopia, presenting a de novo pathogenic variant in the OFD1 gene. Furthermore, to the best of our knowledge, this is the first report of autistic behavior in a female patient with OFD1 syndrome. We propose that autistic behavior should be considered a potential feature of this syndrome and that active screening for early signs of autism might prove beneficial for OFD1 syndrome patients.

Atypical presentations of 22q11.2 deletion syndrome: explaining the genetic defects and genome architecture.

22q11.2 deletion syndrome, the most common microdeletion syndrome, exhibits a broad range of phenotypes, implying a cumbersome diagnosis due to atypical or paucisymptomatic presentations. We present two atypical cases of 22q11.2 deletion syndrome and suggest a preferential occurrence of the breakpoints in regions poor in repetitive elements of SINE/Alu family.

Re-emerging concepts of immune dysregulation in autism spectrum disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by communication and social interaction deficits, and by restricted interests and stereotyped, repetitive behavior patterns. ASD has a strong genetic component and a complex architecture characterized by the interplay of rare and common genetic variants. Recently, increasing evidence suggest a significant contribution of immune system dysregulation in ASD. The present paper reviews the latest updates regarding the altered immune landscape of this complex disorder highlighting areas with potential for biomarkers discovery as well as personalization of therapeutic approaches. Cross-talk between the central nervous system and immune system has long been envisaged and recent evidence brings insights into the pathways connecting the brain to the immune system. Disturbance of cytokine levels plays an important role in the establishment of a neuroinflammatory milieu in ASD. Several other immune molecules involved in antigen presentation and inflammatory cellular phenotypes are also at play in ASD. Maternal immune activation, the presence of brain-reactive antibodies and autoimmunity are other potential prenatal and postnatal contributors to ASD pathophysiology. The molecular players involved in oxidative-stress response and mitochondrial system function, are discussed as contributors to the pro-inflammatory pattern. The gastrointestinal inflammation pathways proposed to play a role in ASD are also discussed. Moreover, the body of evidence regarding some of the genetic factors linked to the immune system dysregulation is reviewed and discussed. Last, but not least, the epigenetic traits and their interactions with the immune system are reviewed as an expanding field in ASD research. Understanding the immune-mediated pathways that influence brain development and function, metabolism, and intestinal homeostasis, may lead to the identification of robust diagnostic or predictive biomarkers for ASD individuals. Thus, novel therapeutic approaches could be developed, ultimately aiming to improve their quality of life.

Clinical and genomic findings in brain heterotopia: Report of a pediatric patient cohort from Romania.

Brain heterotopia is a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to a severe clinical picture (drug-resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors. In the present study, a cohort of 15 pediatric patients with brain heterotopia were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Most of the patients had epileptic seizures, often difficult to control with one antiepileptic drug; another frequent characteristic in the cohort was developmental delay or intellectual disability, in some cases associated with behavioral problems. The genomic studies revealed an interstitial 22q11.2 microduplication, an anomaly not reported previously in heterotopia patients. Comparing the cohort of the present study with that of a previous series of heterotopia patients, both adult and pediatric, similar aspects, such as the high frequency of drug-resistant epilepsy were observed as well as some differences, such as no systemic malformations and no cases with fatal evolution. The current findings add new data to existing knowledge on a rare heterogeneous disorder. The detailed clinical description, including the epilepsy phenotypes, and genomic profiles bring new insights into a group of disorders, yet to be fully understood.

Determinants of satisfaction with the detection process of autism in Europe: Results from the ASDEU study.

LAY ABSTRACT: Professional guidance and support in response to first concerns appears to be an important predictor of the level of satisfaction with the detection process of autism in young children. In this study, we analyzed the views of 1342 family members, including 1278 parents, who completed an online survey form collecting information about their experience and satisfaction with the early detection of autism in their child. Specifically, we were interested in how specific experiences with the detection process relate to the satisfaction with it and whether we could identify important predictors of satisfaction. The detection process is an emotionally charged period for parents, often described as painful, chaotic, and lengthy. A better understanding of their experiences is important to take appropriate action to improve the detection process. In our sample, the level of satisfaction with the detection process varied greatly from one respondent to another. Among the different experiences we considered, whether or not respondents received professional guidance and support in response to first concerns explained most of this variation. We also found that difficulty finding information about detection services, lack of professional guidance and support in response to first concerns, having to find a diagnostic service on one's own, and longer delays between confirmation of concerns and first appointment with a specialist were experiences associated with a greater likelihood of being unsatisfied. The findings of this study highlight the importance of the parent-professional relationship in the detection process and have important practical implications for health administrations to improve the detection process.

Autism and severe clinical phenotype in a patient with 8p21.2p11.21 deletion: Case report and literature review.

Interstitial 8p deletions were previously described, in literature and databases, in approximately 30 patients with neurodevelopmental disorders. We report on a novel patient with a 8p21.2p11.21 deletion presenting a clinical phenotype that includes severe intellectual disability, microcephaly, epilepsy, and autism, the latter having been rarely associated with this genetic defect.

Pallister-Killian Syndrome versus Trisomy 12p-A Clinical Study of 5 New Cases and a Literature Review.

Pallister-Killian syndrome (PKS) is a rare, sporadic disorder defined by a characteristic dysmorphic face, pigmentary skin anomalies, intellectual disability, hypotonia, and seizures caused by 12p tetrasomy due to an extra isochromosome 12p. We present three cases of PKS and two cases of trisomy 12p to illustrate and discuss features rarely cited in the literature, present certain particularities that not yet been cited, and analyze the differences between entities. Moreover, we present alternative methods of diagnosis that could be easily used in daily practice. Features not yet or rarely reported in PKS literature include marked excess of hair on the forehead and ears in the first months of life, a particular eye disorder (abnormal iris color with pointed pupil), connective tissue defects, repeated episodes of infection and autonomic dysfunction, endocrine malfunction as a possible cause of postnatal growth deficit, more complex sensory impairments, and mild early myoclonic jerks. After performing different combinations of tests, we conclude that MLPA (follow-up kit P230-B1) or array CGH using DNA extracted from a buccal swab is a reliable method of diagnosis in PKS and we recommend either one as a first intention diagnostic test. In cases without major defects associated (suspicion trisomy 12p), subtelomeric MLPA should be performed first.

The Phenotypic Spectrum of 15q13.3 Region Duplications: Report of 5 Patients.

Chromosome 15q13.3 microduplications are associated with a wide spectrum of clinical presentations ranging from normal to different neuropsychiatric conditions, such as developmental delay (DD), intellectual disability (ID), epilepsy, hypotonia, autism spectrum disorders (ASD), attention-deficit hyperactivity disorder, and schizophrenia. The smallest region of overlap for 15q13.3 duplications encompasses the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, a strong candidate for the behavioral abnormalities. We report on a series of five patients with 15q13.3 duplications detected by chromosomal microarray. The size of the duplications ranged from 378 to 537 kb, and involved the CHRNA7 gene in all patients. The most common clinical features, present in all patients, were speech delay, autistic behavior, and muscle hypotonia; DD/ID was present in three patients. One patient presented epileptic seizures; EEG anomalies were observed in three patients. No consistent dysmorphic features were noted. Neuroimaging studies revealed anomalies in two patients: Dandy-Walker malformation and a right temporal cyst. 15q13.3 duplications are associated with various neuropsychiatric features, including speech delay, hypotonia, ASD, and ID, also present in our patient group. Our study brings detailed clinical and molecular data from five ASD patients with 15q13.3 microduplications involving the CHRNA7 gene, contributing to the existing knowledge about the association of 15q13.3 duplications with neuropsychiatric phenotypes.

Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies.

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.

Treatment of Epilepsy Associated with Common Chromosomal Developmental Diseases.

Chromosomal diseases are heterogeneous conditions with complex phenotypes, which include also epileptic seizures. Each chromosomal syndrome has a range of specific characteristics regarding the type of seizures, EEG findings and specific response to antiepileptic drugs, significant in the context of the respective genetic etiology. Therefore, it is very important to know these particularities, in order to avoid an exacerbation of seizures or some side effects. In this paper we will present a review of the epileptic seizures and antiepileptic treatment in some of the most common chromosomal syndromes.

Predictive factors in early onset schizophrenia.

Schizophrenia is a neurodevelopmental disorder, characterized by impairment in reasoning, affectivity and social relationships. Although the diagnosis of schizophrenia in children and adolescents has been challenged for many years, at present childhood-onset schizophrenia is considered and accepted as a clinical and biological continuum with the adult-onset disorder. The present study aimed to evaluate the influence of biological (psychiatric family history, perinatal factors), and socio-demographic factors (area of residence, gender) on the age at onset and severity of symptomatology in children and adolescent with schizophrenia. The data were collected from 2016 to 2019 and included 148 children and adolescents with schizophrenia. Data were analysed with statistical software (IBM SPSS 22, JASP and JAMOVI, Linear Regression Model, χ² tests, t-test, U-test). A positive familial history for psychiatric diseases was an important risk factor both for an early onset and for the severity of symptoms. Urbanicity was another studied risk factor, 61% of patients being from urban areas; no statistically significant correlations between urbanicity and age at onset and severity of symptoms were identified. There was no statistically significant gender difference in terms of age at onset and severity of symptoms. Moreover, no statistically significant correlations were found between perinatal factors and age at onset and severity of symptoms. Positive psychiatric family history showed a statistically significant influence on age at onset and symptoms severity in children and adolescent schizophrenia; no statistical significant impact on the aforementioned schizophrenia aspects was observed for urbanicity, gender or perinatal factors.

Early Detection, Diagnosis and Intervention Services for Young Children with Autism Spectrum Disorder in the European Union (ASDEU): Family and Professional Perspectives.

Early services for ASD need to canvas the opinions of both parents and professionals. These opinions are seldom compared in the same research study. This study aims to ascertain the views of families and professionals on early detection, diagnosis and intervention services for young children with ASD. An online survey compiled and analysed data from 2032 respondents across 14 European countries (60.9% were parents; 39.1% professionals). Using an ordinal scale from 1 to 7, parents' opinions were more negative (mean = 4.6; SD 2.2) compared to those of professionals (mean = 4.9; SD 1.5) when reporting satisfaction with services. The results suggest services should take into account child's age, delays in accessing services, and active stakeholders' participation when looking to improve services.

Correction to: Early Detection, Diagnosis and Intervention Services for Young Children with Autism Spectrum Disorder in the European Union (ASDEU): Family and Professional Perspectives.

The original version of this article unfortunately contained a mistake in one of the co-author's family name. The correct name should be María Victoria Martín-Cilleros instead of María Victoria Cilleros-Martín.

Neurofibromatosis type 1 associated with moyamoya syndrome. Case report and review of the literature.

Neurofibromatosis type 1 (NF1) is a genetic disorder with a very heterogeneous clinical picture, affecting central nervous system, skin and bone system. Cerebrovascular lesions, such as moyamoya syndrome, are rarely seen in NF1. Approximately 250 children with NF1 and moyamoya syndrome have been reported. The clinical picture includes hemiparesis, hemianopsia, paresthesia, seizures, speech disorders, and intellectual disability. In this paper, we report on a 6-year-old girl with NF1 and moyamoya syndrome, with a brief review of the existing literature.

The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.