European journal of medical genetics最新文献

{"title":"Two families with spondylo-epi-metaphyseal dysplasia due to compound heterozygocity in the vWFA domain of MATN3","authors":"","doi":"10.1016/j.ejmg.2024.104972","DOIUrl":"10.1016/j.ejmg.2024.104972","url":null,"abstract":"<div><p>Heterozygous variants of <em>MATN3</em> is one of the common causes of multiple epiphyseal dysplasia (MED). Here we report three individuals from two unrelated families who harbor compound heterozygous variants in <em>MATN3</em> (p.Arg121Trp and p.Val220Ala). Contrary to the MED phenotype, these individuals exhibit spondyloepimetaphyseal dysplasia (SEMD) resembling the phenotypes caused by homozygous <em>MATN3</em> variants. Clinical manifestations included short stature, aggravating genu varum, joint laxity, and spinal abnormalities. Radiographic findings were distinct from typical MED. These compound heterozygous variants in the von Willebrand factor A domain of <em>MATN3</em> expand the phenotypic spectrum associated with <em>MATN3</em>, and suggest that extreme MATN3 dysfunction resulting from dual variants can lead to a specific pattern of SEMD.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000648/pdfft?md5=a3e0a2d5fd5456fb9607145433c071bc&pid=1-s2.0-S1769721224000648-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239622","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":"Novel CTR9 germline pathogenic splice site variant in siblings with Wilms tumor from Tanzania","authors":"","doi":"10.1016/j.ejmg.2024.104973","DOIUrl":"10.1016/j.ejmg.2024.104973","url":null,"abstract":"<div><div>Wilms tumor is the most common childhood renal malignancy. Though mostly non-genetic, it can be syndromic with the involvement of many Wilms tumor predisposing genes and non-syndromic with the involvement of four genes: <em>WT1</em>, <em>REST, TRIM28,</em> and <em>CTR9</em>. Familial and bilateral Wilms tumors do occur, but these are rare. So far, four Wilms tumor families with pathogenic variants in the <em>CTR9</em> gene have been described, all (presumably) inherited from unaffected fathers, and three leading to deletion of exon 9. We are reporting female siblings, of whom one has a bilateral Wilms tumor, with a novel pathogenic splice site variant in the <em>CTR9</em> gene, leading to deletion of exon 9, and inherited from their asymptomatic father. The loss of heterozygosity in the tumor was confirmed. In conclusion, <em>CTR9</em> pathogenic variants are a very rare cause of Wilms tumors and typically result in familial Wilms tumors.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400065X/pdfft?md5=70b5699e9b0e63dd77631839ef4ead00&pid=1-s2.0-S176972122400065X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282353","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":"Economic evaluation of extended panel analysis in cancer patients with historical NHS diagnostic germline genetic testing – A modeling study based on real-world data","authors":"","doi":"10.1016/j.ejmg.2024.104969","DOIUrl":"10.1016/j.ejmg.2024.104969","url":null,"abstract":"<div><h3>Background</h3><p>The South West Thames Centre for Genomics implemented a wider diagnostic Next Generation Sequencing (NGS) gene panel for eligible cancer patients undergoing diagnostic testing whilst restricting data analysis and reporting for BRCA1/BRCA2/PALB2/CHEK2 1100delC only as per contemporaneous guidelines. This study investigated the cost-utility of reanalyzing existing diagnostic grade extended panel data for truncating germline pathogenic variants (GPVs) in known moderate risk cancer susceptibility genes (CSGs) and performing follow-up genetic testing for first-degree relatives if patients have an identified CSG allele.</p></div><div><h3>Methods</h3><p>Reanalysis of existing NGS data was undertaken in 889 samples from cancer patients contemporaneously eligible through the NHS England National Genomic Test Directory (NGTD) codes R207 (ovarian) or R208 (breast) who had tested negative for <em>BRCA1/BRCA2/PALB2</em> and <em>CHEK2</em> 1100delC founder variant. We modeled the cost and health outcomes for comparisons between: 1. Extending reanalysis to <em>ATM</em> truncating GPVs (partial extended testing) versus historical genetic testing, and 2. Extending analysis to <em>ATM</em> truncating GPV/<em>BRIP1</em> truncating <em>GPV</em>/<em>CHEK2</em> truncating GPV excluding <em>CHEK2</em> 1100delC/<em>RAD51C</em> truncating GPV/<em>RAD51D</em> truncating GPV (full extended testing) versus historical genetic testing.</p></div><div><h3>Results</h3><p>For partial extended testing, the ICER compared with historical genetic testing was UK£49,671/QALY. For full extended testing, the ICER compared with historical genetic testing of historical genetic testing was UK£5716/QALY. The full extended testing remained cost-effective with a 30% increase in genetic testing cost.</p></div><div><h3>Conclusion</h3><p>Where existing NGS data for cancer susceptibility genes is stored to diagnostic standard in UK laboratories, this study suggests it is cost-effective to analyze, report and clinically manage patients and relatives by extended analysis to an 8-gene panel compared to the historical genetic testing.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000612/pdfft?md5=50cb4a23057fdd510638f4a901c6c944&pid=1-s2.0-S1769721224000612-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167594","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":"Mutation spectrum of Tyrosinemia type I in Iran, A retrospective cohort study","authors":"","doi":"10.1016/j.ejmg.2024.104970","DOIUrl":"10.1016/j.ejmg.2024.104970","url":null,"abstract":"<div><p>Hereditary Tyrosinemia Type 1 (HT1) is a genetic disorder characterized by an autosomal recessive inheritance pattern, caused by mutations in the fumarylacetoacetate hydrolase (<em>FAH</em>) gene, which results in a deficiency of fumarylacetoacetase. In our study, we identified a total of 15 mutations, including 12 newly discovered and 3 previously reported pathogenic mutations, in a cohort of 19 Iranian patients with the acute form of HT1. Out of the 12 novel variants identified, 11 were missense variants: p.Asp126His, p.Gln75Glu, p.Leu385Pro, p.Ser92Thr, p.Leu96Arg, p.Val167Glu, p.Ala94Asp, p.Gly353Trp, p.Ser164Pro, p.Glu86His and p.Ala163Pro. Additionally, there was one nonsense variant, p.Try244X, that had not been previously reported. Interestingly, the Arg237X variant was found to be particularly prevalent in this study. Notably, three exons, namely exons 9, 3, and 6, exhibited a higher frequency of mutations. All of the identified variants are presumed to result in loss of function, impacting the clinical signs, disease progression, increasing tyrosine level, and the specific location of the mutation. Our study has provided valuable insights into the mutation spectrum of variants associated with HT1 disease which is reported for the first time from Iran. This information can facilitate the development of targeted mutation screening protocols, focusing on the most prevalent mutations within specific regions or ethnic groups.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000624/pdfft?md5=2ff717015c567d947ff336c82e8aaf24&pid=1-s2.0-S1769721224000624-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167268","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":"Biallelic potential disease-causing missense variants in TAF1A in two siblings with infantile restrictive cardiomyopathy","authors":"","doi":"10.1016/j.ejmg.2024.104968","DOIUrl":"10.1016/j.ejmg.2024.104968","url":null,"abstract":"<div><p><em>TAF1A</em>, a gene encoding a TATA-box binding protein involved in ribosomal RNA synthesis, is a candidate gene for pediatric cardiomyopathy as biallelic <em>TAF1A</em> variants were reported in two families with affected individuals. Here, we report a third family with two siblings who presented with infantile restrictive cardiomyopathy and carried biallelic missense variants in <em>TAF1A</em> (NM_001201536.1:c.1021G&gt;A p.(Gly341Arg) and c.781A&gt;C p.(Thr261Pro)). Additional shared clinical features in the siblings included feeding intolerance, congenital leukoencephalopathy, ventriculomegaly and concern for primary immunodeficiency. The first-born sibling passed away at 6 months of age due to complications of hemophagocytic lymphohistiocytosis (HLH) whereas the second sibling underwent cardiac transplantation at 1 year of age and is currently well. We compare the clinical and molecular features of all the <em>TAF1A</em> associated cardiomyopathy cases. Our study adds evidence for the gene-disease association of <em>TAF1A</em> with autosomal recessive pediatric cardiomyopathy.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000600/pdfft?md5=1959d5f52aa2dc3b3ac19996e8660d8d&pid=1-s2.0-S1769721224000600-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105651","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":"Digital clubbing without hypoxia for lysinuric protein intolerance","authors":"","doi":"10.1016/j.ejmg.2024.104967","DOIUrl":"10.1016/j.ejmg.2024.104967","url":null,"abstract":"<div><p>Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in <em>SLC7A7</em> and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the <em>SLC7A7</em>, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, <em>HPGD</em> and <em>SLCO2A1</em>. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with <em>SLC7A7</em> may be attributed to the mechanism of increased PGE2 production.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000594/pdfft?md5=4840da5efaafd99cd62004e70f0a1188&pid=1-s2.0-S1769721224000594-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141990764","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":"The first Brazilian clinical report of Kleefstra syndrome, including semicircular canals agenesis as a possible phenotype expansion","authors":"","doi":"10.1016/j.ejmg.2024.104966","DOIUrl":"10.1016/j.ejmg.2024.104966","url":null,"abstract":"<div><h3>Objective</h3><p>to report the first case series of Brazilian children diagnosed with Kleefstra syndrome, present a possible phenotype expansion to the syndrome and to raise physicians' awareness for this rare disease.</p></div><div><h3>Results</h3><p>seven patients with confirmed KS were evaluated, including 5 males and 2 females. Abnormal prenatal findings were observed in 4 patients. Most patients were born at term, with normal birth measurements. All patients had neurodevelopmental delay and 6 evolved with intellectual disability. Hearing loss was present in 57.1% of patients and 28.7% had congenital heart disease. In males, cryptorchidism was present in 75%. Despite the facial dysmorphisms, only 2 out of 7 patients had a pre-test clinical suspicion of KS. One specific patient presented bilateral agenesis of the semicircular canals, a very rare ear manifestation in Kleefstra syndrome, representing a possible phenotype expansion of the syndrome.</p></div><div><h3>Conclusion</h3><p>this report aims to promote awareness among physicians evaluating patients in a context of neurodevelopmental delay or congenital malformations, especially congenital heart defects. We also highlight a possible phenotype expansion of the syndrome, with a case of semicircular anomaly, not reported in this syndrome so far.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000582/pdfft?md5=371bdbb5d8d212248eacb6a51f55b3fc&pid=1-s2.0-S1769721224000582-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987676","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":"The history of the international rare diseases research consortium (IRDiRC) and its conferences","authors":"","doi":"10.1016/j.ejmg.2024.104935","DOIUrl":"10.1016/j.ejmg.2024.104935","url":null,"abstract":"<div><p>Individual researchers and consortia have been studying rare diseases for several decades. However, the rare disease community can be very fragmented mainly due to the large heterogeneity of rare diseases. Indeed, for many diseases, there is a very limited amount of researchers and resources available. Concerted efforts to organize the rare disease community and funding were emerging in several countries but so far, international coordination was rather limited. The International Rare Diseases Research Consortium (IRDiRC) aims to correct this. A part of this requires bringing rare disease researchers together for an international conference.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000272/pdfft?md5=91fd47c80bcc2493bcaf40d58874aae5&pid=1-s2.0-S1769721224000272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140597441","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":"Cardiovascular abnormalities in patients with SHANK3 pathogenic variants: Beyond neurodevelopmental disorders and epilepsy","authors":"","doi":"10.1016/j.ejmg.2024.104965","DOIUrl":"10.1016/j.ejmg.2024.104965","url":null,"abstract":"<div><p>Neurodevelopmental disorders have been linked to numerous genes, particularly pathogenic variants in genes encoding postsynaptic scaffolding proteins, like <em>SHANK3</em>. This study aims to provide insights into the cardiovascular profile of patients with pathogenic <em>SHANK3</em> variants, expanding beyond the well-established associations with neurodevelopmental disorders and epilepsy. We conducted a prospective study involving patients affected by neurodevelopmental disorders with pathogenic <em>SHANK3</em> variants. Comprehensive cardiovascular assessments were performed and molecular genetic testing included chromosomal microarray followed by clinical exome sequencing. We identified five patients with <em>de novo SHANK3</em> variants, all of whom exhibited cardiac involvement, including myocardial dysfunction, congenital heart disease (patent ductus arteriosus), and a case of postictal atrial fibrillation. Our findings emphasize an elevated risk of cardiovascular abnormalities in patients with <em>SHANK3</em> pathogenic variants compared to prior reports. Despite their young age, these patients displayed significant cardiac abnormalities. The study highlights the necessity of integrating cardiac evaluation and ongoing cardiovascular monitoring into multidisciplinary care, facilitating early detection of heart failure and assessment of the risk of sudden unexpected death in epilepsy (SUDEP). Further research is needed to elucidate the underlying mechanisms of cardiac manifestations in <em>SHANK3</em> mutation carriers.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000570/pdfft?md5=a1784ad42810e49b34751a97798e94bb&pid=1-s2.0-S1769721224000570-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878534","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":"Demystifying gene(tic) therapies","authors":"","doi":"10.1016/j.ejmg.2024.104963","DOIUrl":"10.1016/j.ejmg.2024.104963","url":null,"abstract":"<div><p>This article summarizes the discussion from a session entitled “Demystifying gene therapies” that was held at the joint RE(ACT) congress and IRDiRC conference, 14–15 March 2023 in Berlin, Germany. The focus of this session was to discuss the changing landscape of genetic therapies and whether current resources exist to provide adequate education to stakeholders, such as researchers, clinicians, patient advocates, legislators, as well as the patients and their families. The goal of this article is not to provide a comprehensive overview of the current landscape in genetic therapies, but rather to highlight resources that may be useful to help “demystify” the myriad of genetic therapeutic approaches.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000557/pdfft?md5=03051b5d5212d03cc724e72f838a6890&pid=1-s2.0-S1769721224000557-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787617","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}