European journal of medical genetics最新文献

{"title":"Hypohidrotic ectodermal dysplasia caused by an intragenic duplication in EDAR","authors":"","doi":"10.1016/j.ejmg.2024.104982","DOIUrl":"10.1016/j.ejmg.2024.104982","url":null,"abstract":"<div><div>Hypohidrotic Ectodermal Dysplasia is a syndrome with hypotrichosis, hypohidrosis, and hypodontia as the main symptoms. The prevalence is estimated to one in 5000–10,000 persons. In 10–15% the disease is caused by pathogenic variants in <em>EDAR</em>, and most of the known causal variants to date are missense or nonsense variants. We present a patient with classic Hypohidrotic Ectodermal Dysplasia and mammary gland aplasia with a duplication within <em>EDAR</em> as the likely cause. The duplication is <em>de novo</em> in the patient, and genome sequencing of DNA extracted from blood has revealed that the duplication is in tandem conformation, most likely entailing an altered EDAR protein with a dominant negative effect. This is to our knowledge the first report of an intragenic duplication in <em>EDAR</em> as causal for Hypohidrotic Ectodermal Dysplasia.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated variant re-evaluation is labor-balanced and gives clinically relevant results: Hereditary cardiac disease as a use case","authors":"","doi":"10.1016/j.ejmg.2024.104981","DOIUrl":"10.1016/j.ejmg.2024.104981","url":null,"abstract":"<div><h3>Background</h3><div>Genetic findings influence clinical care of patients suspected of hereditary cardiac diseases. As additional knowledge arises over time, the classification of genetic variants may change. The labor cost associated with systematic manual reevaluation for reported variants is substantial. We applied an automated variant classifier for reevaluation of previous reported variants to assess how such tools may assist in manual reevaluation.</div></div><div><h3>Methods</h3><div>Historically (2010–2022), patients (N = 2987) suspected of inherited cardiomyopathies or ion-channel disorders were screened for genetic variants in at least one of up to 114 genes. We had reported 1455 unique variants, of which 742 were among the 14 most relevant genes. In the 14-gene-group, we compared our reported classification to that of an autoclassifier and manually reevaluated variant classification of all variants. Among the remaining genes (N = 100), only variants where the autoclassifier predicted change of clinical impact, such as variant of uncertain significance to likely pathogenic or oppositely, were manually reevaluated.</div></div><div><h3>Results</h3><div>We identified 9% (66/742) of variants with clinical impact in the 14-gene-group. Of these, 91% could have been identified solely evaluating the 120 variants where the autoclassifier had predicted a change of clinical impact. In the 100 remaining genes, a change of clinical impact was identified in 3% (22/713) after manual reevaluation.</div></div><div><h3>Conclusion</h3><div>Using an autoclassifier reduces the workload to identify variants likely to have a change in variant class with clinical impact. Hence, we recommend using such tools to identify the variants most relevant to manually reevaluate to improve patient care.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focal segmental glomerulosclerosis associated with undescribed mutation in the LMX1B gene","authors":"","doi":"10.1016/j.ejmg.2024.104980","DOIUrl":"10.1016/j.ejmg.2024.104980","url":null,"abstract":"<div><div>A 50-year-old woman presented with nephrotic proteinuria and preserved glomerular filtration rate. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) and glomerular basement membrane thinning. Her brother has a long history of chronic kidney disease, formerly diagnosed with minimal change disease, and eventually received a kidney allograft, developing high-grade proteinuria and decline in kidney function. FSGS was found by biopsy. Lastly, one paternal uncle suffered from the same condition, but he declined a biopsy. A genetic test identified a novel missense mutation in <em>LMX1B</em>, c.349G &gt; A:p(Gly117Ser). Thus, the present series of cases shows a familial <em>LMX1B</em>-associated nephropathy presenting with FSGS.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASXL1-related Bohring-Optiz syndrome complicated by persistent neonatal pulmonary hypertension and abnormal alveoli formation","authors":"","doi":"10.1016/j.ejmg.2024.104978","DOIUrl":"10.1016/j.ejmg.2024.104978","url":null,"abstract":"<div><div>Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and formation of abnormal alveoli that was confirmed by autopsy. A female neonate was born by cesarean section at 37 weeks and 2 days of gestation and found to have a nevus flammeus, exophthalmos, abnormal palate, retraction of the mandible, and a posture characteristic of BOS. The patients had severe PPHN requiring inhalation of nitric oxide. Genetic testing revealed a <em>de novo</em> frameshift variant in <em>ASXL1</em>. Autopsy revealed that the lung was at the saccular stage, equivalent to 28–34 weeks of gestation. This is the first report to present pathological evidence of immaturity of the lung that may be associated with PPHN in a patient with BOS caused by a variant in <em>ASXL1</em>.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the clinical spectrum of CNTNAP2-related neurodevelopmental disorders: A case series and a literature appraisal","authors":"","doi":"10.1016/j.ejmg.2024.104979","DOIUrl":"10.1016/j.ejmg.2024.104979","url":null,"abstract":"<div><div>Biallelic pathogenic variants in <em>CNTNAP2</em>, a gene encoding the contactin-associated protein-like 2, have been reported in patients with various clinical presentations including intellectual disability (ID), autistic spectrum disorders (ASD), psychiatric disorders, and focal epilepsy rarely associated to focal cortical dysplasia.</div><div>We report four children carrying novel biallelic <em>CNTNAP2</em> pathogenic variants. They present global developmental delay, psychiatric disorders, and focal epilepsy. All patients displayed brain MRI abnormalities consistent with focal temporal dysplasia. One patient had a temporal resection before the availability of genetic testing. Focal cortical dysplasia represents a frequent finding related to focal refractory epilepsy in <em>CNTNAP2</em> affected patients, and surgery seems to be ineffective in this setting. The genetic testing could therefore be impactful on treatment choices in refractory focal epilepsies.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telehealth for rare disease care, research, and education across the globe: A review of the literature by the IRDiRC telehealth task force","authors":"","doi":"10.1016/j.ejmg.2024.104977","DOIUrl":"10.1016/j.ejmg.2024.104977","url":null,"abstract":"<div><div>The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs). The Task Force reviewed related literature published from January 2017 to August 2023, and identified various models and implementation strategies of TH for RD. The Task Force highlighted the reported value and benefits of using TH for RDs, along with the limitations and opportunities. The number of publications sharply increased since 2021, coinciding with the onset of the COVID-19 pandemic, which forced the rapid adoption of TH in many healthcare settings. One of the major benefits of TH for RDs lies in its capacity to surmount geographical barriers, which helps in overcoming the constraints posed by limited numbers and geographical dispersion of specialists. This was evident during the pandemic when TH was used to maintain a level of continued medical care and research when face-to-face visits were severely restricted. TH, through which clinical research can be decentralized, can also facilitate and enhance RD research by decreasing burden, expanding access, and enhancing efficiency. This will be especially beneficial when coupled with the adoption of digital health technologies, such as mobile health (mHealth) and wearable devices for remote monitoring (i.e., surveillance of outpatient data transmitted through devices), along with big data solutions. TH has also been shown to be an effective means for RD education and peer mentoring, enabling local health care providers (HCPs) to care for RD patients, which indirectly ensures that RD patients get the expertise and multidisciplinary care they need. However, limitations and weaknesses associated with using TH for RD care and research were also identified, including the inability to perform physical examinations and build relationships with HCPs. Therefore, TH has been recommended as a complement to, rather than substitute for, face-to-face consultations. There is also a concern that TH may lead to an amplification of health disparities and inequities related to social determinants of health for those with RDs due to lack of access to TH technologies, inadequate digital literacy, and geographical, socio-cultural, and linguistic barriers. Finally, the Task Force also discussed evidence and knowledge gaps that will benefit from future research efforts to help advance and expand the use of TH for RD care, research, and education.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lessons learned from the RE(ACT) conference on medical devices for rare diseases","authors":"","doi":"10.1016/j.ejmg.2024.104976","DOIUrl":"10.1016/j.ejmg.2024.104976","url":null,"abstract":"<div><div>The field of rare disease therapeutics has witnessed significant growth in recent years, highlighting the need for diverse therapeutic approaches to cater to the unique needs of individuals with rare diseases. Rare disease therapies encompass a broad spectrum of interventions, including orphan medicinal products, orphan medical devices, rehabilitative therapies, and digital therapeutics, with the lines between these categories blurring. This paper covers the session of the RE (ACT)-IRDiRC Conference 2023 and delves into the landscape of orphan medical device research and development, shedding light on the challenges and opportunities in this burgeoning field. It provides a short overview of the different international legislations in the field. In addition, it highlights several exemplary orphan medical devices. The first example is an exoskeleton for boys with Duchenne Muscular Dystrophy, enabling them to maintain arm functionality and independence. Another example presented was an EEG device linked to an app detecting seizures in rare epilepsy conditions, which alerts caregivers to seizures in real-time but also facilitates objective seizure reporting for clinicians, aiding in diagnosis and treatment optimization. It also showcases the role of gamification and enabling technologies in addressing rare diseases, by showing a game designed for children with cystic fibrosis, and a telemedicine system for rehabilitation therapy. Both solutions aim to improve patients' understanding of their conditions and enhance their self-management. In conclusion, this paper underscores the critical need for patient-centric orphan and pediatric medical devices to provide therapeutic options for individuals with rare diseases. It highlights the impact of existing devices on enhancing the quality of life for rare disease patients and emphasizes the necessity for greater incentives and support for research and development in this field.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel germline Pregnane X Receptor (PXR) variant predisposing to Hodgkin lymphoma in two siblings","authors":"","doi":"10.1016/j.ejmg.2024.104975","DOIUrl":"10.1016/j.ejmg.2024.104975","url":null,"abstract":"<div><div>Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-κB pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL.</div><div>The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM_003889.3:c.811G&gt;A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased <em>PXR</em> expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-PCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells.</div><div>Patients with homozygous <em>PXR</em> variant showed significantly high expression compared to <em>PXR</em> wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). <em>PXR</em> homozygous HRS cells had significantly higher PXR expression compared to <em>PXR</em> wild-type HRS cells (p &lt; 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous <em>PXR</em> HRS cells showed increased PXR expression in nucleus (p &lt; 0.001).</div><div>PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous <em>PXR</em> HL cases. This study provided clinical evidence to previously reported <em>Sxr</em>^{<em>−/−</em>} mice model that develop multifocal lymphomas, had an aberrantly increased NF-κB expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ITGB4-Related pyloric atresia without epidermolysis in two siblings","authors":"","doi":"10.1016/j.ejmg.2024.104971","DOIUrl":"10.1016/j.ejmg.2024.104971","url":null,"abstract":"<div><div>Pyloric atresia is a rare gastrointestinal anomaly with an incidence of 1/100,000 in live births. It is usually seen as an isolated condition or in combination with other congenital or hereditary anomalies. Autosomal recessive inherited either fatal or non-fatal variants of pyloric atresia with epidermolysis bullosa are known due to mutations in <em>ITGA6</em>, <em>ITGB4,</em> and <em>PLEC</em> genes. <em>ITGB4</em> gene mutation was recently identified in 5 siblings in 2 families associated with familial isolated pyloric atresia. Herein, we present two siblings who had pyloric atresia together with a homozygous variant in the <em>ITGB4</em> gene and without epidermolysis bullosa. The development of isolated familial pyloric atresia without epidermolysis bullosa may occur due to homozygous variants of the <em>ITGB4</em> gene. Detection of more variants in this gene may help to establish a genotype-phenotype correlation and may suggest the <em>ITGB4</em> gene in patients who have pyloric atresia without epidermolysis bullosa.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Kleefstra syndrome cohort phenotype characteristics: Prevalence insights from caregiver-reported outcomes","authors":"","doi":"10.1016/j.ejmg.2024.104974","DOIUrl":"10.1016/j.ejmg.2024.104974","url":null,"abstract":"<div><p>Kleefstra syndrome (KLEFS1) is a rare genetic neurodevelopmental disorder affecting multiple body systems. It continues to be under-researched, and its prevalence remains unknown. This paper builds on the international KLEFS1 cohort of 172 individuals based on the caregiver-reported outcomes collected within the online data collection platform GenIDA and reports the occurrence, frequency and severity of symptoms in KLEFS1. The study clearly shows the importance of caregiver-reported outcomes collections in the rare disease domain. Moreover, the study emphasizes the need for more specific and enhanced data collection methods, suggesting recommendations to optimize caregiver-reported registries and foster an even more profound understanding of rare diseases.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000661/pdfft?md5=e94c78b3aeabf529c0f697b4bc6baa91&pid=1-s2.0-S1769721224000661-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}