De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy.

Nine out of 19 genes encoding GABAA receptor subunits have been linked to monogenic syndromes characterized by seizures and developmental disorders. Previously, we reported the de novo variant p.(Thr300Ile) in GABRA4 in a patient with epilepsy and neurodevelopmental abnormalities. However, no new cases have been reported since then. Through an international collaboration, we collected molecular and phenotype data of individuals carrying de novo variants in GABRA4. Patients and their parents were investigated either by exome or genome sequencing, followed by targeted Sanger sequencing in some cases. All variants within the transmembrane domain, including the previously reported p.(Thr300Ile) variant, were characterized in silico and analyzed by molecular dynamics (MD) simulation studies. We identified three novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile). The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells. Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4). MD simulations of the three variants within the transmembrane domain of the receptor indicate that sub-microsecond scale dynamics differ between wild-type and mutated subunits. Taken together, our findings further corroborate an association between GABRA4 and a neurological phenotype including variable neurodevelopmental, behavioral and epileptic abnormalities.

Smart hospital: achieving interoperability and raw data collection from medical devices in clinical routine.

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. A Comprehensive Integration of raw Data and Structured Medical Information has not yet Been Established. The aim of this project was to design and implement an interoperable database (cardio-vascular-information-system, CVIS) for the automated integration of al medical device data (parameters and raw data) in cardio-vascular medicine. Methods: The CVIS serves as a data integration and preparation system at the interface between the various devices and the hospital IT infrastructure. In our project, we were able to establish a database with integration of proprietary device interfaces, which could be integrated into the electronic health record (EHR) with various HL7 and web interfaces. Results: In the period between 1.7.2020 and 30.6.2022, the data integrated into this database were evaluated. During this time, 114,858 patients were automatically included in the database and medical data of 50,295 of them were entered. For technical examinations, more than 4.5 million readings (an average of 28.5 per examination) and 684,696 image data and raw signals (28,935 ECG files, 655,761 structured reports, 91,113 x-ray objects, 559,648 ultrasound objects in 54 different examination types, 5,000 endoscopy objects) were integrated into the database. Over 10.2 million bidirectional HL7 messages (approximately 14,000/day) were successfully processed. 98,458 documents were transferred to the central document management system, 55,154 materials (average 7.77 per order) were recorded and stored in the database, 21,196 diagnoses and 50,353 services/OPS were recorded and transferred. On average, 3.3 examinations per patient were recorded; in addition, there are an average of 13 laboratory examinations. Discussion: Fully automated data integration from medical devices including the raw data is feasible and already creates a comprehensive database for multimodal modern analysis approaches in a short time. This is the basis for national and international projects by extracting research data using FHIR.

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

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. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval.

The Role of RYR2 in Atrial Fibrillation.

Background. 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. Genome-wide association studies identified several loci in AF patients, indicating the complex genetic architecture of this disease. In rare cases, familial forms of AF have been described. Today, pathogenic variants in at least 11 different genes are associated with monogenic AF. Case presentation. The 37-year-old male patient presented to our emergency department with AF. At the age of 35, he had already been diagnosed with paroxysmal AF. Additionally, his 34-year-old brother had also been diagnosed with AF as well as nonobstructive hypertrophic cardiomyopathy. Moreover, the patient's father was diagnosed with AF in his twenties. Transthoracic echocardiography and cardiac MRI revealed a reduced systolic left ventricular ejection without any signs of hypertrophic cardiomyopathy. Genetic testing identified the heterozygous missense variants c.3371C > T, p.(Pro1124Leu) in RYR2 (NM_001035.3) and c.2524C > A, p.(Pro842Thr) in HCN4 (NM_005477.3) in the patient's and his brother's DNA. Discussion. This case of familial AF helps to strengthen the role of RYR2 as a disease gene in the context of AF. Although the variant in RYR2 needs to be classified formally as variant of unknown significance, we regard it as probably disease-causing due to the previously published data. As RYR2 has already been identified as a possible target for prevention and therapy of AF, the knowledge of variants in RYR2 might become even more crucial for individual molecular therapies in the future.

Telemedical monitoring in patients with inborn cardiac disease - experience of a tertiary care centre.

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. METHODS: Patients were screened once they had been referred to our outpatient department for rare cardiac diseases between January 2020 and May 2022. Those patients who underwent genetic testing and were consequently diagnosed with a genetic disorder were included in this study. Their medical records were evaluated regarding implanted cardiac electronic devices and findings in the telemedical monitoring. RESULTS: 304 patients were seen in our outpatient department for rare cardiac diseases in the mentioned period. In 100 cases, genetic testing was performed. 10 patients (10%) with an identified inborn cardiac disease were monitored via telemedicine until the end of May 2022. 4 patients were monitored by implantable loop recorders (ILR), 4 patients were monitored by Implantable Cardioverter Defibrillators (ICD), and 2 patients received both devices. Clinical relevant arrhythmias making medical intervention necessary were identified in 4 cases. In two cases, data interpretation was hampered by sinus tachycardia caused by physical exercise. DISCUSSION: Telemonitoring of the heart rhythm by medical devices is beneficial for patients with monogenic heart diseases. Especially, when the indication for an ICD is not clear, implantation of a telemonitored ILR can be a suitable choice. However, rhythm analysis can be challenging in young patients who are physically active.

Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants.

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. RESULTS: Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry's disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). CONCLUSION: Genetic screening for Fabry's disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

Genetic and phenotypic spectrum in the NONO-associated syndromic disorder.

The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.

Fetal Bradycardia Caused by Monogenic Disorders-A Review of the Literature.

Introduction: The standard obstetric definition of fetal bradycardia is a sustained fetal heart rate < 110 bpm over at least 10 min. Fetal bradycardia can be the first and only prenatal presentation of a heart disease. We present an overview on different genetic disorders that should be taken into consideration in case of diagnosed fetal bradycardia. Methods: A literature review was conducted using a PubMed- and OMIM-based search for monogenetic disorders causing fetal bradycardia in September 2022. Results: The review on the literature identified nine monogenic diseases that could lead to fetal bradycardia. Four of these disorders can be associated with extracardiac findings. Discussion: Genetic testing should be considered in cases with fetal bradycardia, especially in cases of additional extracardiac findings. Broad sequencing techniques and improved prenatal phenotyping could help to establish a diagnosis in an increasing number of cases.

Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes.

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. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic de novo, rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in PKD1L1 and ZIC3 were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in LMBRD1 and DNAH17, respectively, were prioritized. In another family, an ultra-rare de novo variant in WDR47 was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in WDR47, but no further individuals with biallelic variants in DNAH17 or LMBRD1. Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes PKD1L1 and ZIC3 and suggests DNAH17, LMBRD1, and WDR47 as potential genes involved in laterality defects.

Myocarditis or inherited disease? - The multifaceted presentation of arrhythmogenic cardiomyopathy.

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. An additional performed myocardial biopsy confirmed a lymphocytic inflammatory reaction. Subsequently, the patient experienced cardiac arrest because of ventricular fibrillation and was resuscitated. As a result, she received an implantable cardioverter defibrillator, and repeated ablations of recurrent ventricular tachycardia were performed. After four years, molecular genetic testing identified the heterozygous, likely pathogenic nonsense variant c.4789G > T, p.(Glu1597*) in DSP (NM_004415.4). Based on this finding, ACM could be diagnosed, and a heart transplantation was performed only a few months later because of rapid disease progression. DISCUSSION: Truncating variants in DSP have been associated with fulminant progression of arrhythmia. However, the currently used ARVC task force criteria are inadequate to detect DSP-associated ACM with left dominant presentation. Moreover, the initial diagnosis of myocarditis may distract from a more extensive search for other causes. Consequently, in cases of recurrent or unusually prolonged myocarditis, especially if present without detected pathogens, molecular genetic testing should be considered.

It Is Not Carved in Stone-The Need for a Genetic Reevaluation of Variants in Pediatric Cardiomyopathies.

(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. (2) Methods: Medical records of patients and their relatives were screened for clinical and genetic information at the Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich. Patients without an identified genetic variant were excluded from further analyses. Previously reported variants were reevaluated by the ACMG criteria in November 2021. (3) Results: Data from 167 patients or relatives of patients with childhood-onset cardiomyopathy from 137 families were analyzed. In total, 45 different genetic variants were identified in 71 individuals. Classification changed in 29% (13/45) with the greatest shift in "variants of unknown significance" to "(likely) benign" (9/13). (4) Conclusions: In patients with childhood-onset cardiomyopathies, nearly a third of reported genetic variants change mostly to more benign classes upon reclassification. Given the impact on patient management and cascade screening, this finding underlines the importance of continuous genetic counseling and variant.

A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.

Variants in γ-aminobutyric acid A (GABAA ) 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. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early-onset drug-resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore-forming domain, shows accelerated desensitization and a lack of seizure-protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.

There is more to it than just congenital heart defects - The phenotypic spectrum of TAB2-related syndrome.

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. METHODS: Cases in whom whole exome sequencing was executed at our institute between January 2015 and June 2021 were screened for disease-causing variants in TAB2. Additionally, a PubMed-based review of the literature was performed in December 2021 in order to give an updated clinical overview of the TAB2-associated phenotypic spectrum, including our cases. RESULTS: We identified three cases with syndromic CHD caused by different heterozygous loss-of-function variants in TAB2. In one of these cases, the variant was inherited by a healthy father. A comparison with published cases highlights that most patients were affected by structural and/or arrhythmic heart disease (about 90%) while about two third of all cases had syndromic comorbidity especially connective tissue defects and dysmorphic abnormalities. CONCLUSION: Our findings indicate a variable expressivity as well as reduced penetrance of TAB2-associated CHD. Disease-causing variants in TAB2 should be considered in cases with isolated CHD but also in syndromic CHD with connective tissue abnormalities. However, prediction of the patients' clinical outcome solely based on the variant in TAB2 is still extremely challenging.

Do children with congenital heart defects meet the vaccination recommendations? Immunisation in children with congenital heart defects.

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. Therefore, immunisations in these children are essential. MATERIALS AND METHODS: Individuals were recruited at the outpatient centre of the Department of Congenital Heart Defects and Pediatric Cardiology at the German Heart Center Munich in the time between February 2016 and February 2017. Included were children between 23 months and 17 years and a diagnosis of CHD. The vaccination certificate aimed to assess the immunization status. RESULTS: In total, 657 children with CHD were included and analysed. Regarding primary immunisation, only 34 % (n = 221) of the children reached the complete vaccination status within the allowed catch-up time. Among these primary immunisation rates, vaccinations against Hepatitis B, Meningococci, Varicella and Pneumococci were found to have the lowest coverage with all being below 80%. The vaccination rate was partly influenced by the previously performed number of surgeries but not by the diagnosis of specific genetic diseases. At the age of school entry, the immunisation rate in children with CHD was also lower than in the comparable healthy population. CONCLUSION: The vaccination coverage rate in children with CHD is lower than in comparable healthy children, although this is a vulnerable patient group. Further education of parents and treating physicians of children with CHD regarding vaccination is still needed.

A case report of RASA1-associated inherited lymphoedema with recurrent life-threatening lymphangitis.

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 RASA1. This clinical case highlights the possible complications of RASA1-associated lymphatic malformation in a female suffering from recurrent life-threatening septic lymphangitis. CASE SUMMARY: A 23-year-old female patient presented with congenital lymphoedema of the lower right extremity. At the age of eight, she first suffered from an episode of lymphangitis. Thereafter, she developed recurrent episodes of lymphangitis predominately occurring during menstruation and culminating into severe and life-threatening septicaemias. Due to the menstrual association, endometriosis was suspected but could not be confirmed. Furthermore, angiography could not detect any sign of arteriovenous fistula. Single-Photon-Emission-Computed-Tomography confirmed absent major lymphatics of the right leg with severely impaired and prolonged dermal lymphatic backflow. Genetic testing identified a disease-causing variant in the RASA1 gene. DISCUSSION: To our knowledge, this is the first case of recurrent septic lymphangitis with close relation to menstruation in a female with RASA1-associated lymphatic malformation. Due to the possible de novo or somatic origin of a pathogenic variant, a genetic disease should be considered in spite of an unremarkable family history or a localized lymphoedema. Although there is no curative therapy available yet, the knowledge of the underlying genetic defect is important for interdisciplinary patient care and might be crucial for individual molecular therapies in the future.

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

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. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. RESULTS: We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles. CONCLUSION: Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

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. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

Reclassification of genetic variants in children with long QT syndrome.

BACKGROUND: Genes encoding cardiac ion channels or regulating proteins have been associated with the inherited form of long QT syndrome (LQTS). Complex pathophysiology and missing functional studies, however, often bedevil variant interpretation and classification. We aimed to evaluate the rate of change in variant classification based on current interpretation standards and dependent on clinical findings. METHODS: Medical charts of children with a molecular genetic diagnosis of LQTS presenting at our centers were retrospectively reviewed. Reinterpretation of originally reported variants in genes associated with LQTS was performed based on current knowledge (March 2019) and according to the "Standards and Guidelines for the Interpretation of Sequence Variants" by the ACMG 2015. RESULTS: About 84 distinct (likely) pathogenic variants identified in 127 patients were reinterpreted. In 12 variants (12/84, 14.3%), classification changed from (likely) pathogenic to variant of unknown significance (VUS). One of these variants was a hypomorphic allele escaping the standard variant classification. Individuals with variants that downgraded to VUS after reevaluation showed significantly lower Schwartz scores and QTc intervals compared to individuals with unchanged variant characterization. CONCLUSION: This finding confirms genetic variant interpretation as a dynamic process and underlines the importance of ongoing genetic counseling, especially in LQTS patients with minor clinical criteria.

A novel pathogenic variant in MYO18B associating early-onset muscular hypotonia, and characteristic dysmorphic features, delineation of the phenotypic spectrum of MYO18B-related conditions.

Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing. We present the fifth case of MYO18B-associated disease in a newborn male patient. Trio exome sequencing identified the previously unreported homozygous nonsense variant c.6433C>T, p.(Arg2145*) in MYO18B (NM_032608.5). While most phenotypic features of our patient align with previously reported cases, we describe the prenatal features for the first time. Taking the phenotypic description of our patient into account, we propose that the core phenotype comprises a severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features.