Publications by authors named "Dominik Westphal"

Background: Yellow nail syndrome (YNS) is a rare disorder characterized by a triad of yellow dystrophic nails, lymphedema, and chronic lung disease. Most patients present in adulthood, with only a few congenital or familial cases described. The cause of YNS remains largely unknown, although defects in lymphatic vessel development are suggested to play a significant role.

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Background: Aortic stenosis (AS) induces cardiac remodeling upon chronic left ventricular (LV) pressure overload. Here, we analyzed the clinical outcome of patients undergoing transcatheter aortic valve replacement (TAVR) for symptomatic AS with regard to varying LV hypertrophy patterns. Moreover, we investigated the genetic influence on development of different hypertrophy patterns, measured by polygenic risk scores (PRS).

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Background: Exome sequencing has been established as a fundamental tool in genetic diagnostics. It may also provide information about variants in genes unrelated to the primary purpose, so-called secondary findings. Especially, diagnoses of unnoticed inborn cardiac diseases are of high clinical relevance due to therapeutic options in context of prevention of sudden cardiac death.

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  • * A 3-year study, TRANSLATE NAMSE, analyzed data from 1,577 patients, revealing that 32% received molecular diagnoses involving 370 distinct causes, primarily uncommon.
  • * The research showed that combining next-generation sequencing with advanced phenotyping methods improved diagnostic efficiency and helped identify new genotype-phenotype associations, particularly in neurodevelopmental disorders.
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  • Nine out of 19 genes that code for GABA receptor subunits are linked to disorders associated with seizures and developmental issues.
  • The study identified three new de novo missense variants in the GABRA4 gene in patients with epilepsy and various neurodevelopmental problems, highlighting a connection between these genetic changes and neurological symptoms.
  • Molecular dynamics simulations showed that the mutated GABRA4 subunits behave differently than the normal ones, supporting the role of this gene in causing a range of neurological conditions.
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Introduction: Today, modern technology is used to diagnose and treat cardiovascular disease. These medical devices provide exact measures and raw data such as imaging data or biosignals. So far, the Broad Integration of These Health Data into Hospital Information Technology Structures-Especially in Germany-is Lacking, and if data integration takes place, only non-Evaluable Findings are Usually Integrated into the Hospital Information Technology Structures.

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Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes.

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. Atrial fibrillation (AF) is a common arrhythmia in elderly patients and is associated with increased risk of mortality. The pathogenesis of AF is complex and based on multiple genetic and environmental factors.

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  • - The standard definition of fetal bradycardia is a sustained heart rate of less than 110 beats per minute for at least 10 minutes, which can indicate underlying heart disease.
  • - A review identified nine genetic disorders potentially linked to fetal bradycardia, with four of those also showing signs beyond just heart issues.
  • - Genetic testing is recommended for cases of fetal bradycardia, especially when other physical symptoms are present, as advanced sequencing could aid in accurate diagnosis.
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Background: The number of cardiologically relevant genetic findings will continue to increase. This is due to the use of high-throughput sequencing techniques and the critical role of incidental findings in cardiac disease genes. Telemedicine can be a useful diagnostic tool to monitor the heart rhythm of patients with inborn cardiac diseases.

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  • The NONO protein plays a critical role in gene regulation, particularly in RNA metabolism and DNA repair, and its pathogenic variants can lead to a rare X-linked syndrome.
  • In a study, researchers identified six males with NONO gene variants and reviewed 16 previously documented cases, highlighting common symptoms like developmental delays and heart issues.
  • The investigation expanded known symptoms of the NONO syndrome to include epilepsy and blood-related disorders, and confirmed that loss-of-function mutations are the underlying cause of these issues.
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Background: Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far.

Material And Methods: We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center.

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The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility.

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Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is now usually referred to as arrhythmogenic cardiomyopathy (ACM) because of the possible left and biventricular affection. In recent years, it has been shown that early-stage ACM, especially in women carrying a disease-causing variant in the DSP gene, may present with clinical signs of myocarditis.

Case Presentation: The female patient was diagnosed with myocarditis based on arrhythmia and findings on magnetic resonance imaging at the age of 24 years.

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(1) Background: In cardiomyopathies, identification of genetic variants is important for the correct diagnosis and impacts family cascade screening. A classification system was published by the American College of Medical Genetics and Genomics (ACMG) in 2015 to standardize variants' classification. The aim of the study was to determine the rate of reclassification of previously identified variants in patients with childhood-onset cardiomyopathies.

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Variants in γ-aminobutyric acid A (GABA ) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4-subunit, has not been associated with a monogenic condition. However, preclinical evidence points toward seizure susceptibility.

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  • - The study investigates the genetic factors underlying congenital heart disease by screening nearly 3,900 mouse gene mutations for cardiac issues, finding 705 lines with conditions like arrhythmia and myocardial hypertrophy.
  • - Out of these, 486 genes are newly linked to heart dysfunction, including variants of unknown relevance (VUR), with specific mutations in five genes (Casz1, Dnajc18, Pde4dip, Rnf38, Tmem161b) leading to notable structural heart defects.
  • - Using data from the UK Biobank, the research further confirms the role of the DNAJC18 gene in heart function, highlighting its loss as linked to changes in cardiac performance, thus identifying new potential targets for understanding
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Background: Congenital heart defects (CHD) are the most common birth defect and disease-causing variant in TAB2 have found to be associated with isolated CHD. Recently, it became evident that pathogenic, mostly loss-of-function variants in TAB2 can also cause syndromic CHD that includes connective tissue anomalies. The number of published cases is limited posing a challenge for counseling affected patients and their relatives.

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Background: Most cases of lymphoedema are secondary to other causes, while cases of primary lymphoedema, in particular that of congenital origin, are uncommon. Limited genetic disorders are so far known to be associated with lymphatic malformation including mutations in . This clinical case highlights the possible complications of -associated lymphatic malformation in a female suffering from recurrent life-threatening septic lymphangitis.

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Introduction: Congenital heart defects (CHDs) are the most common congenital malformations. Patients with CHD have a higher morbidity and mortality rate and are at greater risk for infectious diseases. The risk might even be higher if complex CHD occurs and if CHD is associated with additional co-morbidities.

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Background: ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.

Methods: To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes.

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Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs.

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Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

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  • The study focuses on how the classification of genetic variants linked to Long QT Syndrome can change over time based on new interpretations and clinical findings.
  • A review of medical records for children diagnosed with LQTS led to the reevaluation of 84 genetic variants; 14.3% of these were downgraded to 'variant of unknown significance.'
  • The results emphasize that genetic variant classification is not static and highlights the necessity for continuous genetic counseling for patients with less severe symptoms.
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