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Contains fulltext : 307090.pdf (Publisher’s version ) (Closed access), Radboud University, 05 juli 2024, Promotores : Bokhoven, J.H.L.M. van, Nadif Kasri, N., Majoie, H.J., 283 p.

Contains fulltext : 293172.pdf (Publisher’s version ) (Open Access), Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development. Although several genes and contiguous gene syndromes are implicated in the monogenic etiology of isolated SHFM, the disorder remains genetically unexplained for many families and associated genetic loci. We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years. We combined well-established approaches including microarray-based copy number variant analysis and fluorescence in situ hybridization coupled with optical genome mapping and whole genome sequencing. This strategy identified a complex structural variant (SV) comprising a 165-kb gain of 15q26.3 material ([GRCh37/hg19] chr15:99795320-99960362dup) inserted in inverted position at the site of a 38-kb deletion on Xq27.1 ([GRCh37/hg19] chrX:139481061-139518989del). In silico analysis suggested that the SV disrupts the regulatory framework on the X chromosome and may lead to SOX3 misexpression. We hypothesize that SOX3 dysregulation in the developing limb disturbed the fine balance between morphogens required for maintaining AER function, resulting in SHFM in this family.

Radboud University, 16 mei 2023, Promotores : Bokhoven, J.H.L.M. van, Nadif Kasri, N. Co-promotor : Schubert, D., Contains fulltext : 292275.pdf (Publisher’s version ) (Closed access)

01 juli 2023, Item does not contain fulltext, Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Contains fulltext : 300240.pdf (Publisher’s version ) (Open Access), Dravet syndrome is a severe epileptic encephalopathy, characterized by (febrile) seizures, behavioural problems and developmental delay. Eighty per cent of patients with Dravet syndrome have a mutation in SCN1A, encoding Nav1.1. Milder clinical phenotypes, such as GEFS+ (generalized epilepsy with febrile seizures plus), can also arise from SCN1A mutations. Predicting the clinical phenotypic outcome based on the type of mutation remains challenging, even when the same mutation is inherited within one family. This clinical and genetic heterogeneity adds to the difficulties of predicting disease progression and tailoring the prescription of anti-seizure medication. Understanding the neuropathology of different SCN1A mutations may help to predict the expected clinical phenotypes and inform the selection of best-fit treatments. Initially, the loss of Na+-current in inhibitory neurons was recognized specifically to result in disinhibition and consequently seizure generation. However, the extent to which excitatory neurons contribute to the pathophysiology is currently debated and might depend on the patient clinical phenotype or the specific SCN1A mutation. To examine the genotype-phenotype correlations of SCN1A mutations in relation to excitatory neurons, we investigated a panel of patient-derived excitatory neuronal networks differentiated on multi-electrode arrays. We included patients with different clinical phenotypes, harbouring various SCN1A mutations, along with a family in which the same mutation led to febrile seizures, GEFS+ or Dravet syndrome. We hitherto describe a previously unidentified functional excitatory neuronal network phenotype in the context of epilepsy, which corresponds to seizurogenic network prediction patterns elicited by proconvulsive compounds. We found that excitatory neuronal networks were affected differently, depending on the type of SCN1A mutation, but did not segregate according to clinical severity. Specifically, loss-of-function mutat

Radboud University, 25 april 2022, Promotores : Bokhoven, J.H.L.M. van, Engelen, B.G.M. van Co-promotor : Wansink, D.G., Contains fulltext : 247699.pdf (Publisher’s version ) (Closed access)

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Contains fulltext : 248864.pdf (Publisher’s version ) (Open Access), Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified SOD1 (superoxide dismutase 1), an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased MTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point toward an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and MTOR-dependent autophagy.Abbreviations: APO: apocynin; ATG: autophagy related; BAF: bafilomycin A(1); BSO: buthionine sulfoximine; CV: coefficient of variation; DIV: days i

Contains fulltext : 252015.pdf (Publisher’s version ) (Closed access), Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Contains fulltext : 251368.pdf (Publisher’s version ) (Open Access), Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A(+/-)). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A(+/-) neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A(+/-) cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.

Item does not contain fulltext, BACKGROUND: As the requirements for collaboration in primary care increase, effective interprofessional teamwork between GPs and other primary care professionals is crucial. The need for more training in interprofessional collaborative competencies is widely recognised. However, existing competency frameworks do not sufficiently specify interprofessional collaboration to guide interprofessional competency development. AIM: To reach consensus among GPs and other primary care professionals on interprofessional competencies that GP and GP trainees should learn. DESIGN & SETTING: A qualitative consensus study among Dutch GPs and other primary care professionals, all with expertise in primary care interprofessional collaborative practice. METHOD: Three nominal group sessions were held, each resulting in its own group consensus on GP interprofessional collaborative competencies. The researchers conducted a content analysis to merge and thematise the prioritised competencies into one list. Participants prioritised this list of competencies. A pre-set cut-off point was applied to determine the overall consensus on core GP interprofessional competencies. RESULTS: Eighteen professionals from nine different disciplines participated. The content analysis resulted in 31 unique competencies, of which 14 competencies were prioritised in the final ranking into the following three main themes: (1) professional identity development and role definition by the GP (three competencies); (2) developing and executing shared care plans for individual patients (six competencies); and (3) initiating and maintaining interprofessional collaborative partnerships (five competencies). CONCLUSION: An interprofessional group of experts reached consensus on 14 competencies within three themes. This framework provides a stepping stone for GPs to focus on their development regarding interprofessional collaboration.

Contains fulltext : 282703.pdf (Publisher’s version ) (Open Access), The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10-and EMC1-related disease.

Item does not contain fulltext, Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum. Over the last years, targeted and clinical exome sequencing in our center has identified 41 CACNA1A variants. Ultimately, variants were considered pathogenic or likely pathogenic in 23 cases, with most phenotypes ranging from episodic or progressive ataxia to more complex ataxia syndromes, as well as intellectual disability and epilepsy. In two cases, the causality of the variant was discarded based on non-segregation or an alternative diagnosis. In the remaining 16 cases, the variant was classified as uncertain, due to lack of opportunities for segregation analysis or uncertain association with a non-classic phenotype. Phenotypic variability and the large number of VUS make CACNA1A a challenging gene for neurogenetic diagnostics. Accessible functional read-outs are clearly needed, especially in cases with a non-classic phenotype.

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Contains fulltext : 283195.pdf (Publisher’s version ) (Open Access), BACKGROUND: Young-onset dementia (YOD) has many underlying etiologies, leading to a large heterogeneity in first symptoms. This makes it difficult for general practitioners (GPs) to recognize YOD. OBJECTIVE: Identify early symptoms that are more common in the pre-diagnostic phase of YOD. METHODS: We performed a case-control study nested in a primary-care registry on 89 cases and 162 matched controls, where we compared symptoms of people with YOD up to 5 years before diagnosis to their matched control group without YOD. The variables included in this study were International Classification of Primary Care codes and symptoms extracted from written GP notes and categorized in groups. We used Generalized Equation Estimation to analyze symptom's time-trajectories and logistic regression and ROC-curves to analyze differences in number of symptom categories reported. RESULTS: Cognitive symptoms were more common in people with YOD 5 years before diagnosis, affective symptoms 4 years before diagnosis, social symptoms 3 years, behavioral symptoms 2 years, and daily functioning disturbances 1 year before diagnosis. The ROC-curve suggested that reporting two or more symptom categories at the GP gave the best trade-off between sensitivity (85%) and specificity (77%), for the highest percentage of correctly diagnosed persons. CONCLUSION: This study showed people with YOD present differently than people without YOD. However, it may still be difficult for GPs to use these symptom categories to distinguish people with YOD, since the symptoms also occur in people with other diseases. A combination of reported symptom categories increases the probability of an underlying cause of YOD.

Radboud University, 27 september 2021, Promotores : Bokhoven, J.H.L.M. van, Nadif Kasri, N. Co-promotor : Schubert, D., Contains fulltext : 236413 .pdf (Publisher’s version ) (Open Access)

Contains fulltext : 234992.pdf (Publisher’s version ) (Closed access), PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

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Item does not contain fulltext, Fragile X syndrome (FXS) is the most prevalent inherited cause of intellectual disability (ID) and autism spectrum disorder (ASD). Many studies have been conducted over the years, however, in Indonesia there is relatively less knowledge on the prevalence of FXS. We reviewed all studies involving FXS screening and cascade testing of the high-risk population in Indonesia for two decades, to elucidate the prevalence, as well as explore the presence of genetic clusters of FXS in Indonesia. The prevalence of FXS in the ID population of Indonesia ranged between 0.9-1.9%, while in the ASD population, the percentage was higher (6.15%). A screening and cascade testing conducted in a small village on Java Island showed a high prevalence of 45% in the ID population, suggesting a genetic cluster. The common ancestry of all affected individuals was suggestive of a founder effect in the region. Routine screening and subsequent cascade testing are essential, especially in cases of ID and ASD of unknown etiology in Indonesia.

Item does not contain fulltext, The intrinsic regenerative capacity of skeletal muscle makes it an excellent target for cell therapy. However, the potential of muscle tissue to renew is typically exhausted and insufficient in muscular dystrophies (MDs), a large group of heterogeneous genetic disorders showing progressive loss of skeletal muscle fibers. Cell therapy for MDs has to rely on suppletion with donor cells with high myogenic regenerative capacity. Here, we provide an overview on stem cell lineages employed for strategies in MDs, with a focus on adult stem cells and progenitor cells resident in skeletal muscle. In the early days, the potential of myoblasts and satellite cells was explored, but after disappointing clinical results the field moved to other muscle progenitor cells, each with its own advantages and disadvantages. Most recently, mesoangioblasts and pericytes have been pursued for muscle cell therapy, leading to a handful of preclinical studies and a clinical trial. The current status of (pre)clinical work for the most common forms of MD illustrates the existing challenges and bottlenecks. Besides the intrinsic properties of transplantable cells, we discuss issues relating to cell expansion and cell viability after transplantation, optimal dosage, and route and timing of administration. Since MDs are genetic conditions, autologous cell therapy and gene therapy will need to go hand-in-hand, bringing in additional complications. Finally, we discuss determinants for optimization of future clinical trials for muscle cell therapy. Joined research efforts bring hope that effective therapies for MDs are on the horizon to fulfil the unmet clinical need in patients.

Contains fulltext : 231703.pdf (publisher's version ) (Open Access), Schizophrenia is a psychiatric disorder with a typical onset occurring during adolescence or young adulthood. The heterogeneity of the disorder complicates our understanding of the pathophysiology. Reduced cortical synaptic densities are commonly observed in schizophrenia and suggest a role for excessive synaptic elimination. A major pathway hypothesised to eliminate synapses during postnatal development is the complement system. This review provides an overview of genetic and functional evidence found for the individual players of the classical complement pathway. In addition, the consequences of the absence of complement proteins, in the form of complement protein deficiencies in humans, are taken into consideration. The collective data provide strong evidence for excessive pruning by the classical complement pathway, contributing to cognitive impairment in schizophrenia. In future studies, it will be important to assess the magnitude of the contribution of complement overactivity to the occurrence and prevalence of phenotypic features in schizophrenia. In addition, more insight is required for the exact mechanisms by which the complement system causes excessive pruning, such as the suggested involvement of microglial engulfment and degradation of synapses. Ultimately, this knowledge is a prerequisite for the development of therapeutic interventions for selective groups of schizophrenia patients.

Contains fulltext : 235399.pdf (Publisher’s version ) (Closed access), EDEM3 encodes a protein that converts Man(8)GlcNAc(2) isomer B to Man(7-5)GlcNAc(2). It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man(8)GlcNAc(2) isomer B to Man(7)GlcNAc(2), consistent with loss of EDEM3 enzymatic activity. In human cells, Man(5)GlcNAc(2) to Man(4)GlcNAc(2) conversion is also diminished with an increase of Glc(1)Man(5)GlcNAc(2). Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.

Contains fulltext : 237667.pdf (Publisher’s version ) (Open Access), Micro-electrode arrays (MEAs) are increasingly used to characterize neuronal network activity of human induced pluripotent stem cell (hiPSC)-derived neurons. Despite their gain in popularity, MEA recordings from hiPSC-derived neuronal networks are not always used to their full potential in respect to experimental design, execution, and data analysis. Therefore, we benchmarked the robustness of MEA-derived neuronal activity patterns from ten healthy individual control lines, and uncover comparable network phenotypes. To achieve standardization, we provide recommendations on experimental design and analysis. With such standardization, MEAs can be used as a reliable platform to distinguish (disease-specific) network phenotypes. In conclusion, we show that MEAs are a powerful and robust tool to uncover functional neuronal network phenotypes from hiPSC-derived neuronal networks, and provide an important resource to advance the hiPSC field toward the use of MEAs for disease phenotyping and drug discovery.

Contains fulltext : 237635.pdf (Publisher’s version ) (Open Access), Dysregulation of transcriptional pathways is observed in multiple forms of neurodevelopmental disorders (NDDs), such as intellectual disability (ID), epilepsy and autism spectrum disorder (ASD). We previously demonstrated that the NDD genes encoding lysine-specific demethylase 5C (KDM5C) and its transcriptional regulators Aristaless related-homeobox (ARX), PHD Finger Protein 8 (PHF8) and Zinc Finger Protein 711 (ZNF711) are functionally connected. Here, we show their relation to each other with respect to the expression levels in human and mouse datasets and in vivo mouse analysis indicating that the coexpression of these syntenic X-chromosomal genes is temporally regulated in brain areas and cellular sub-types. In co-immunoprecipitation assays, we found that the homeotic transcription factor ARX interacts with the histone demethylase PHF8, indicating that this transcriptional axis is highly intersected. Furthermore, the functional impact of pathogenic mutations of ARX, KDM5C, PHF8 and ZNF711 was tested in lymphoblastoid cell lines (LCLs) derived from children with varying levels of syndromic ID establishing the direct correlation between defects in the KDM5C-H3K4me3 pathway and ID severity. These findings reveal novel insights into epigenetic processes underpinning NDD pathogenesis and provide new avenues for assessing developmental timing and critical windows for potential treatments.

The Jacobian Conjecture states that if a complex polynomial mapping has a Jacobian matrix whose determinant is a nonzero constant, it has an inverse, which is also a polynomial mapping. In this thesis, we consider the Reduction theorem by Bass, Connel, and Wright proposed in 1982, which states that we can reduce this conjecture to mappings of the form F=X+N, where N is cubic homogeneous. We compare this theorem to a paper written by Hubbers in 1999, who modified their technique to further reduce to a Druzkowski mapping.

Radboud University, 31 augustus 2021, Promotores : Bokhoven, J.H.L.M. van, Schenck, A. Co-promotor : Kramer, J.M., Contains fulltext : 235368.pdf (Publisher’s version ) (Open Access)

Vrijdag 9 april 2021, is deze brief verzonden naar de Informateur en de Fractievoorzitters van VVD, D66, CDA, CU, PvdA, GL en SP met de oproep om een aantal punten inzake biomassa te verankeren in het Regeerakkoord. De brief is ondertekend door een brede coalitie die werkt aan verstandige en hoogwaardige toepassing van biogrondstoffen (biomassa).

Radboud University, 16 december 2020, Promotores : Bokhoven, J.H.L.M. van, Nadif Kasri, N. Co-promotor : Vries, L.B.A. de, Contains fulltext : 226622.pdf (publisher's version ) (Open Access)

Radboud University, 30 oktober 2020, Promotor : Bokhoven, J.H.L.M. van Co-promotores : Schenck, A., Warrenburg, B.P.C. van de, Contains fulltext : 217371.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 220423.pdf (Publisher’s version ) (Closed access), CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.

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Contains fulltext : 229188.pdf (Publisher’s version ) (Closed access), We present a family with three girls presenting similar dysmorphic features, including overgrowth, intellectual disability, macrocephaly, prominent forehead, midface retrusion, strabismus, and scoliosis. Both parents were unaffected, suggesting the presence of an autosomal recessive syndrome. Following exome sequencing, a heterozygous nonsense variant was identified in the NFIX gene in all three siblings. The father appeared to have a low-grade (7%) mosaicism for this variant in his blood. Previously, de novo pathogenic variants in NFIX have been identified in Marshall-Smith syndrome and Malan syndrome, which share distinctive phenotypic features shared with the patients of the present family. This case emphasizes the importance of further molecular analysis especially in familial cases, to exclude the possibility of parental mosaicism.

Contains fulltext : 229068.pdf (Publisher’s version ) (Open Access), Disruption of chromatin structure due to epimutations is a leading genetic etiology of neurodevelopmental disorders, collectively known as chromatinopathies. We show that there is an increasing level of convergence from the high diversity of genes that are affected by mutations to the molecular networks and pathways involving the respective proteins, the disrupted cellular and subcellular processes, and their consequence for higher order cellular network function. This convergence is ultimately reflected by specific phenotypic features shared across the various chromatinopathies. Based on these observations, we propose that the commonly disrupted molecular and cellular anomalies might provide a rational target for the development of symptomatic interventions for defined groups of genetically distinct neurodevelopmental disorders.

Radboud University, 04 december 2020, Promotor : Bokhoven, J.H.L.M. van Co-promotor : Brouwer, A.P.M. de, Contains fulltext : 226624.pdf (publisher's version ) (Open Access)