Publications by authors named "Koolen D"

Article Synopsis
  • This study identifies a new type of autosomal recessive intellectual disability linked to genetic variants in the GTF3C3 gene, which is essential for proper RNA polymerase III activity.
  • Researchers employed various methods, including exome sequencing and Drosophila models, to analyze the effects of GTF3C3 variants found in twelve affected individuals from seven families.
  • The results showed that the variants lead to significant functional losses in the gene, correlating with symptoms like intellectual disability, motor issues, seizures, and brain structure abnormalities.
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The Koolen-de Vries Syndrome Foundation was founded in 2013 with the mission to educate, increase awareness, promote research and develop treatments for individuals living with Koolen-de Vries Syndrome (KdVS) and their families. With this aim, the foundation has focused on: developing scientific resources through patient cell and animal models, providing seed funding to basic and clinical researchers, establishing a natural history study of KdVS and increasing patient engagement. Projects have been prioritized across these areas of focus with an emphasis on expanding international research on KdVS, supporting translational research, establishing an international natural history study and conducting studies to assess patient priorities.

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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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Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures.

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Article Synopsis
  • Rapid exome sequencing (rES) is becoming the go-to genetic test for critically ill patients, especially neonates and young infants, helping quickly identify genetic causes of rare diseases to guide treatment.
  • A study evaluated rES on 575 patients over four years, revealing a significant increase in referrals and a decrease in turnaround time for results, with an overall diagnostic yield of 30.4%.
  • Even when no genetic diagnosis was found, rES still influenced clinical decision-making, highlighting its value for patients of all ages and various rare conditions.
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Objectives: Koolen-de Vries Syndrome (KdVS) is a rare multisystem neurodevelopmental disorder. Ocular manifestations, including strabismus, ptosis, and hyperopia, have been reported in KdVS patients, but detailed clinical data are limited. This study aims to investigate the already known ocular malformations and their frequency while uncovering novel ocular associations.

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The use of variable renewable energy sources to generate electricity introduces a dependency on meteorological factors into power systems. With the renewables share growing globally, often driven by political pressures, the reliability and efficiency of power systems are increasingly affected by this dependency. In this paper, we investigate the impact of the natural variability of meteorological parameters on the European power system in 2030.

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Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53).

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The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English.

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Background: KBG syndrome is caused by haploinsufficiency of and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined.

Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network.

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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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The Koolen-de Vries syndrome (KdVS) is a multisystem disorder characterized by developmental delay, intellectual disability, characteristic facial features, epilepsy, cardiovascular and urogenital malformations, and various musculoskeletal disorders. Scoliosis is a common feature. The aim of this study is to fill the gap in the current knowledge about scoliosis in individuals with KdVS and to provide recommendations for management and follow-up.

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Purpose: GenIDA is an international patient registry for individuals diagnosed with intellectual disability, autism spectrum disorder, and/or epilepsy, which is based on an online questionnaire that is completed by parent caregivers. In this study, the GenIDA data on Koolen-de Vries syndrome (KdVS) was analyzed illustrating the value of GenIDA and patient/caregiver participation in rare genetic neurodevelopmental disorders (NDDs).

Methods: Recruitment was done on the GenIDA website from November 2016 to February 2022.

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Article Synopsis
  • The study investigates a new neurodevelopmental syndrome linked to loss-of-function variants in the ANK2 gene, associated with conditions like intellectual disability and autism.
  • Researchers used CRISPR technology to create human-induced pluripotent stem cells (hiPSCs) with these genetic variants, then differentiated these cells into neurons for further examination.
  • Findings revealed that ANK2-deficient neurons exhibited hyperactivity and lack of synchronization within neuronal networks, along with structural changes that affect their function and adaptability.
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Article Synopsis
  • AMOTL1 is a gene that codes for a protein involved in regulating cell behavior, including how cells stick together and move.
  • A study identified specific mutations in AMOTL1 that are linked to a set of health issues, including orofacial clefting, congenital heart disease, tall stature, ear abnormalities, and gastrointestinal problems.
  • The findings suggest that certain variants in AMOTL1, particularly those affecting a critical region of the protein, are associated with a new syndrome characterized by these conditions.
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Speech and language impairment is core in Koolen-de Vries syndrome (KdVS), yet only one study has examined this empirically. Here we define speech, language, and functional/adaptive behaviour in KdVS; while deeply characterising the medical/neurodevelopmental phenotype in the largest cohort to date. Speech, language, literacy, and social skills were assessed using standardised measures, alongside an in-depth health and medical questionnaire.

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Intellectual disability with or without manifestations of autism and/or epilepsy affects 1-2% of the population, and it is estimated that more than 30-50% of these cases have a single genetic cause. More than 1000 genes and recurrent chromosomal abnormalities are involved in these genetic forms of neurodevelopmental disorders, which often remain insufficiently described in terms of clinical spectrum, associated medical problems, etc., due to their rarity and the often-limited number of patients' phenotypes reported.

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Background: Heterozygous disruptions of were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition.

Methods: Here we phenotyped 28 individuals from 17 families with pathogenic -only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German.

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Article Synopsis
  • De novo truncating and splicing pathogenic variants in the ASXL3 gene lead to various developmental and intellectual challenges, including delays and behavioral issues.
  • The study documents three families with inherited ASXL3-related disorders, detailing specific pathogenic variants affecting the father-son duo, mother-child trio, and a mother-daughter pair.
  • Findings highlight the variability of symptoms within affected families and confirm that ASXL3-related disorders can be inherited.
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Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios.

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Background: Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems.

Methods: To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders.

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Article Synopsis
  • - This research focuses on a neurodevelopmental syndrome linked to pathogenic variants in the Jumonji gene, which results in developmental delays, cognitive impairment, and various other symptoms, highlighting a lack of understanding of its molecular causes.
  • - The study analyzes DNA methylation profiles from 56 controls and 11 patients, revealing a clear differentiation in methylation patterns between patients with pathogenic variants and healthy individuals.
  • - A new DNA methylation signature has been identified as a potential biomarker for the syndrome, which may aid in diagnosis and improve care by distinguishing affected patients from those with variants of uncertain significance.
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