Publications by authors named "Gijs W E Santen"

Article Synopsis
  • ARID1A and ARID1B duplications are linked to Coffin-Siris syndrome, but ARID1B duplications have not been previously associated with a specific clinical phenotype until now.
  • A study analyzed 16 cases of ARID1A and 13 cases of ARID1B duplications, revealing that ARID1A duplications resulted in more severe symptoms, including intellectual disabilities and growth delays, while both groups displayed similar features.
  • The research identified unique DNA methylation patterns in ARID1A duplication patients, which differ from those with loss-of-function variants, suggesting the presence of a distinct clinical phenotype for both ARID1A and ARID1B duplications, indicating a new type of
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Article Synopsis
  • The study highlights the role of the BAF chromatin remodeler, specifically the ARID1A subunit, in cranial neural crest cell (CNCC) specification and its link to Coffin-Siris syndrome (CSS).
  • ARID1A haploinsufficiency disrupts the epithelial-to-mesenchymal transition (EMT) vital for CNCC migration, while ARID1A-BAF regulates enhancers connected to EMT genes, demonstrating that ZIC2 binding at these enhancers relies on ARID1A.
  • The research establishes an important connection between ARID1A and ZIC2 in promoting EMT and successful CNCC delamination, suggesting implications for understanding congenital disorders like CSS.
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The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery.

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Article Synopsis
  • The study highlights the lack of understanding regarding comorbidities in individuals with neurodevelopmental disorders (NDDs), which are crucial for accurate diagnosis and prognosis.
  • PhenomAD-NDD is a newly developed database that compiles comorbid phenotypic data from over 51,000 individuals with NDD, utilizing a standardized classification known as Human Phenotype Ontology (HPO).
  • The findings reveal that congenital anomalies are significantly more common in the NDD population compared to the general population, and highlight that many important phenotypes related to genetic NDDs are not currently documented in existing clinical resources like OMIM.
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Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom heterozygous missense variants in the planar cell polarity gene were detected using exome sequencing. Using several in vitro assays, we show that the p.

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Background: The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications.

Methods: Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay.

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Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.

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Article Synopsis
  • - PhenoScore is an open-source AI framework that combines facial recognition technology and Human Phenotype Ontology data to analyze and quantify phenotypic similarities in individuals.
  • - It successfully identifies distinct phenotypes for most of the 40 syndromes studied and proves to be more effective than previous methods in genotype-phenotype correlation investigations.
  • - PhenoScore also helps clarify roles of specific genetic variants by confirming known phenotypic subgroups in certain genes and providing clinical evidence for different ADNP-related phenotypes.
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DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes.

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Imprinting Disorders (ImpDis) are a group of congenital syndromes associated with up to four different types of molecular disturbances affecting the monoallelic and parent-of-origin specific expression of genomically imprinted genes. Though each ImpDis is characterized by aberrations at a distinct genetic site and a specific set of postnatal clinical signs, there is a broad overlap between several of them. In particular, the prenatal features of ImpDis are non-specific.

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Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing.

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Article Synopsis
  • A study investigates the impact of evaluating rare de novo variants (DNVs) in whole exome sequencing (WES) for patients suspected of having inborn errors of immunity (IEI).
  • In a cohort of 123 patients, systematic assessment of DNVs led to identifying 14 potential candidates linked to immune functions, resulting in molecular diagnoses for some patients.
  • The research advocates for incorporating trio-based sequencing in routine diagnostics, providing evidence that certain loss-of-function mutations contribute to autoinflammatory diseases.
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  • The study focuses on "episignatures," which are unique DNA methylation patterns used as biomarkers for diagnosing various genetic syndromes, particularly neurodevelopmental disorders.
  • Researchers analyzed DNA methylation changes in 65 genetic syndromes, identifying specific differentially methylated probes (DMPs) and regions (DMRs) associated with these conditions.
  • Findings indicated that DMPs and DMRs were mostly located in gene promoters and pathways related to neurodevelopment, highlighting a connection between gene mutations and altered DNA methylation profiles in these disorders.
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Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants.

Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome.

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Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes.

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Background: Severe multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).

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The ACMG framework for variant interpretation is well-established and widely used. Although formal guidelines have been published on the establishment of the gene-disease relationships as well, these are not nearly as widely acknowledged or utilized, and implementation of these guidelines is lagging. In addition, for many genes so little information is available that the framework cannot be used in sufficient detail.

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Article Synopsis
  • Mutations in the AMMECR1 gene have been linked to developmental delays, sensorineural hearing loss (SNHL), and various congenital abnormalities in males.
  • A study presented three female relatives of a male fetus with a deletion in the AMMECR1 gene, all experiencing hearing loss, with one having a soft cleft palate and hip dysplasia.
  • The findings suggest that female carriers of AMMECR1 mutations may exhibit milder symptoms of this genetic condition, as the gene is expressed in the fetal inner ear.
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Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes.

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Aim: Traditional studies focusing on the relationship between pharmacokinetics (PK) and pharmacodynamics necessitate blood draws, which are too invasive for children or other vulnerable populations. A potential solution is to use noninvasive sampling matrices, such as saliva. The aim of this study was to develop a population PK model describing the relationship between plasma and saliva clonazepam kinetics and assess whether the model can be used to determine trough plasma concentrations based on saliva samples.

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TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3's direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants.

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