Publications by authors named "Hellebrekers D"

Article Synopsis
  • Systemic immune-mediated diseases (SIDs) may contribute to dilated cardiomyopathy (DCM), and this study aimed to explore the genetic predispositions present in DCM patients with SIDs.
  • The research involved 183 DCM-SID patients, identifying a significantly higher prevalence of pathogenic genetic variants in these individuals compared to healthy controls and DCM patients without SIDs.
  • Findings suggest that about 17-20% of DCM patients with SIDs have pathogenic variants, particularly truncating variants like TTN, indicating the importance of genetic testing for understanding the causes of immune-related DCM.
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High-throughput sequencing technologies have increasingly led to discovery of disease-causing genetic variants, primarily in postnatal multi-cell DNA samples. However, applying these technologies to preimplantation genetic testing (PGT) in nuclear or mitochondrial DNA from single or few-cells biopsied from in vitro fertilised (IVF) embryos is challenging. PGT aims to select IVF embryos without genetic abnormalities.

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Background: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking.

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Article Synopsis
  • Genetic laboratories currently use diverse workflows to diagnose hereditary and congenital diseases, and this study assesses the potential of genome sequencing (GS) to streamline these processes.
  • The researchers tested GS on 1,000 cases with known genetic variants to evaluate its effectiveness compared to existing methods, finding that GS detected 95% of variants across different categories.
  • The results suggest that adopting a GS-first approach could replace multiple workflows in around 85% of clinical cases, allowing for more efficient and comprehensive diagnostics for rare genetic diseases.
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Experience sampling methods (ESM) using mobile health (mHealth) technology with a smartphone application are increasingly used in clinical practice and research. Still, recommendations are limited in young people, and adaptations may be necessary. Patients with Duchenne muscular dystrophy (DMD) are chronically treated with steroids from a young age.

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Article Synopsis
  • Short-read sequencing can struggle to analyze duplicated genomic regions, making it hard to identify many genetic variants in standard studies.
  • The new method, Chameleolyser, improves the identification of single nucleotide variants, small insertions/deletions, and other genetic events in these complex regions using whole-exome sequencing data.
  • In testing with 41,755 exome samples, the method discovered over 2.5 million rare variants and validated a significant percentage of them, providing molecular diagnoses for several previously undiagnosed patients.
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Background: The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.

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It was previously suggested that increasing the number of genes on diagnostic gene panels could increase the genetic yield in patient with dilated cardiomyopathy (DCM). We explored the diagnostic and prognostic relevance of testing DCM patients with an expanded gene panel. The current study included 225 consecutive DCM patients who had no genetic diagnosis after a 48-gene cardiomyopathy-panel.

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Background: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype.

Objective: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.

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Mitochondrial diseases are the most common inborn errors of metabolism. These severe multisystem disorders cause serious morbidity and mortality. Generally no treatment is available.

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Left ventricular hypertrophy (LVH) has a broad differential diagnosis. Pathogenic variants of mitochondrial DNA are a rare cause of LVH, and cardiac MRI is a powerful technique that may aid in differentiating such rare causes. This case report presents three siblings with a pathogenic variant of the mitochondrially encoded tRNA isoleucine gene.

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Purpose: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.

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Background: Dilated cardiomyopathy (DCM) was considered a monogenetic disease that can be caused by over 60 genes. Evidence suggests that the combination of multiple pathogenic variants leads to greater disease severity and earlier onset. So far, not much is known about the prevalence and disease course of multiple pathogenic variants in patients with DCM.

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The presence of neurocognitive and behavioral problems are common features in various neurogenetic disorders. In Duchenne muscular dystrophy (DMD), these problems have been linked to mutations along the dystrophin gene affecting different brain dystrophin isoforms. However, comparable cognitive and behavioral problems have been found in Neurofibromatosis type 1 (NF1).

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Learning disabilities (LDs) and working memory problems (WM) are common brain-related comorbidities in Duchenne muscular dystrophy (DMD). Despite growing evidence on the efficacy of computerized WM training in children with LDs, research in DMD is lacking. This exploratory study assessed whether training (1) improves dystrophin-associated WM problems in DMD, (2) effects are present at post-intervention, 3 and 8 months follow-up, and (3) improves problems that arise from their LDs.

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Background: In Becker muscular dystrophy evidence for neurocognitive and behavioral comorbidity is evolving. More insight into the extend of these problems is of great importance for early detection and remediation in clinical practice.

Objective: In this study we aimed to describe the neurocognitive and behavioral features of a Dutch adult cohort of BMD patients, and to evaluate correlations to motor function outcomes.

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Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2.

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Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis.

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In a Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants in SLIRP. SLIRP gene encodes a stem-loop RNA-binding protein that regulates mitochondrial RNA expression and oxidative phosphorylation (OXPHOS). A frameshift and a deep-intronic splicing variant reduced the amount of functional wild-type SLIRP RNA to 5%.

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Whole exome sequencing (WES), analyzed with GENESIS and WeGET, revealed a homozygous deletion in the C1QBP gene in a patient with progressive external ophthalmoplegia (PEO) and multiple mtDNA deletions. The gene encodes the mitochondria-located complementary 1 Q subcomponent-binding protein, involved in mitochondrial homeostasis. Biallelic mutations in C1QBP cause mitochondrial cardiomyopathy and/or PEO with variable age of onset.

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Purpose: Accurate interpretation of variants detected in dilated cardiomyopathy (DCM) is crucial for patient care but has proven challenging. We applied a set of proposed refined American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria for DCM, reclassified all detected variants in robust genes, and associated these results to patients' phenotype.

Methods: The study included 902 DCM probands from the Maastricht Cardiomyopathy Registry who underwent genetic testing.

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Variants of the C19ORF12-gene have been described in patients with spastic paraplegia type 43 and in patients with mitochondrial membrane protein-associated neurodegeneration (MPAN), a subtype of neurodegeneration associated with brain iron accumulation (NBIA). In both subtypes optic atrophy and neuropathy have been frequently described. This case report describes a patient with bilateral optic atrophy and severe distal muscle weakness based on motor neuropathy without involvement of the central nervous system.

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Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes.

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Background: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis.

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Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families.

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