Journal of Medical Genetics最新文献

{"title":"Commentary on <i>Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank</i>.","authors":"Pål Møller, Toni T Seppälä, Mev Dominguez-Valentin, Julian Sampson","doi":"10.1136/jmg-2024-110385","DOIUrl":"10.1136/jmg-2024-110385","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Authors' response to the commentary by Kivela <i>et al</i> on Hany <i>et al</i> (2024).","authors":"Alan J Mighell, Chris Inglehearn","doi":"10.1136/jmg-2024-110345","DOIUrl":"https://doi.org/10.1136/jmg-2024-110345","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.","authors":"Sian Ellard, Sian Morgan, Sarah L Wynn, Susan Walker, Andrew Parrish, Rachael Mein, Ana Juett, Joo Wook Ahn, Ian Berry, Emma-Jane Cassidy, Miranda Durkie, Louise Fish, Richard Hall, Emma Howard, Julia Rankin, Caroline F Wright, Zandra C Deans, Richard H Scott, Sue L Hill, Emma L Baple, Robert W Taylor","doi":"10.1136/jmg-2024-110228","DOIUrl":"10.1136/jmg-2024-110228","url":null,"abstract":"<p><strong>Purpose and scope: </strong>The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times.</p><p><strong>Methods of statement development: </strong>A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute.</p><p><strong>Results and conclusions: </strong>We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>UBTF</i> haploinsufficiency associated with <i>UBTF</i>-related global developmental delay and distinctive facial features without neuroregression.","authors":"Xueqian Wang, Bingyu Yang, Shengnan Wu, Qisang Fan, Qing Wang, Dandan Zhang, Hongying Wang, Tao Feng, Haitao Lv, Ting Chen","doi":"10.1136/jmg-2024-110061","DOIUrl":"10.1136/jmg-2024-110061","url":null,"abstract":"<p><strong>Background: </strong>The Upstream Binding Transcription Factor (<i>UBTF</i>) gene encodes two nucleolar proteins, UBTF1 and UBTF2. UBTF1 regulates rRNA transcription by RNA polymerase I, while UBTF2 regulates mRNA transcription by RNA polymerase II. A recurrent de novo dominant mutation c.628G>A (p.Glu210Lys) has been identified as a gain-of-function mutation associated with childhood onset neurodegeneration with brain atrophy (CONDBA). Evidence from large-scale population databases and <i>Ubtf^+/-</i> mouse models indicates that <i>UBTF</i> haploinsufficiency is not tolerated.</p><p><strong>Methods: </strong>Three unrelated patients with global developmental delay and distinctive facial features were recruited for the study. Whole exome sequencing (WES) was performed to identify potential genetic abnormalities. Additionally, copy number variation analysis was conducted based on the WES data.</p><p><strong>Results: </strong>All three patients exhibited intellectual disabilities, social challenges and developmental delays in language and gross motor skills. Distinctive facial features included a wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, a flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip. Additionally, patient C presented with more severe language delay, recurrent hepatic dysfunction and an atrial septal defect. Patient A was found to have a nonsense variant, c.1327C>T (p.R443Ter), in the exon 13 of <i>UBTF</i>. Patients B and C both carried a heterozygous deletion encompassing the <i>UBTF</i> gene.</p><p><strong>Conclusion: </strong>In this study, we analysed the detailed phenotypes associated with <i>UBTF</i> haploinsufficiency, which, to our knowledge, have not been previously reported. We propose that <i>UBTF</i> haploinsufficiency-related global developmental delay and distinctive facial features, without neuroregression, constitute a new syndrome distinct from CONDBA.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"K acetyltransferase 2B (<i>KAT2B</i>) variants can be responsible for early onset steroid-resistant nephrotic syndrome.","authors":"Olivier Niel, Ancuta Caliment, Charlotte Hougardy, Olivier Monestier, Karin Dahan","doi":"10.1136/jmg-2024-110142","DOIUrl":"10.1136/jmg-2024-110142","url":null,"abstract":"<p><p>In children, 15% of nephrotic syndromes are steroid-resistant (SRNS); approximately 30% of early onset SRNS have a genetic origin, with more than 100 causal genes described so far. SRNS can be syndromic, if associated with signs and symptoms affecting other organs or systems, such as the central nervous system, the heart or the eyes. Patients with SRNS are at high risk of chronic kidney disease and progressive renal failure, and as such need multidisciplinary care, centred on renal protection. Recently, K acetyltransferase 2B (<i>KAT2B</i>) loss of function was identified as a risk factor for morphological and functional defects in Drosophila nephrocytes; in vitro knockdown of <i>KAT2B</i> also impaired the adhesion and migration ability of human podocytes.Here we provide the first clinical description of a family affected by a loss of function mutation of <i>KAT2B</i> Clinically, both siblings presented with early onset SRNS and bilateral cataract, without neurological or heart defects. Renal function was maintained in the teenage years; nephrotic-range proteinuria was insensitive to immunosuppressive therapies. Therefore, mutations of <i>KAT2B</i> should be sought in patients with unexplained syndromic SRNS affecting the eye.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canadian College of Medical Geneticists: clinical practice advisory document - responsibility to recontact for reinterpretation of clinical genetic testing.","authors":"Elaine Suk-Ying Goh, Lauren Chad, Julie Richer, Yvonne Bombard, Chloe Mighton, Ron Agatep, Melanie Lacaria, Blaine Penny, Mary Ann Thomas, Ma'n H Zawati, Julie MacFarlane, Anne-Marie Laberge, Tanya N Nelson","doi":"10.1136/jmg-2024-110330","DOIUrl":"https://doi.org/10.1136/jmg-2024-110330","url":null,"abstract":"<p><strong>Background: </strong>Advances in technology and knowledge have facilitated both an increase in the number of patient variants reported and variants reclassified. While there is currently no duty to recontact for reclassified genetic variants, there may be a responsibility. The purpose of this clinical practice advisory document is to provide healthcare practitioners guidance for recontact of previously identified and classified variants, suggest methods for recontact, and principles to consider, taking account patient safety, feasibility, ethical considerations, health service capacity and resource constraints. The target audience are practitioners who order genetic testing, follow patients who have undergone genetic testing and those analysing and reporting genetic testing.</p><p><strong>Methods: </strong>A multidisciplinary group of laboratory and ordering clinicians, patient representatives, ethics and legal researchers and a genetic counsellor from the Canadian Association of Genetic Counsellors reviewed the existing literature and guidelines on responsibility to recontact in a clinical context to make recommendations. Comments were collected from the Canadian College of Medical Geneticists (CCMG) Education, Ethics, and Public Policy, Clinical Practice and Laboratory Practice committees, and the membership at large.</p><p><strong>Results: </strong>Following incorporation of feedback, and external review by the Canadian Association of Genetic Counsellors and patient groups, the document was approved by the CCMG Board of Directors. The CCMG is the Canadian organisation responsible for certifying laboratory and medical geneticists who provide medical genetics services, and for establishing professional and ethical standards for clinical genetics services in Canada.</p><p><strong>Conclusion: </strong>The document describes the ethical and practical factors and suggests a shared responsibility between patients, ordering clinician and laboratory practitioners.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Classification of <i>PTEN</i> germline non-truncating variants: a new approach to interpretation.","authors":"Henri Margot, Natalie Jones, Thibaut Matis, Dominique Bonneau, Tiffany Busa, Françoise Bonnet, Solene Conrad, Louise Crivelli, Pauline Monin, Sandra Fert-Ferrer, Isabelle Mortemousque, Sabine Raad, Didier Lacombe, Frédéric Caux, Nicolas Sevenet, Virginie Bubien, Michel Longy","doi":"10.1136/jmg-2024-109982","DOIUrl":"https://doi.org/10.1136/jmg-2024-109982","url":null,"abstract":"<p><strong>Background: </strong>PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from <i>PTEN</i> pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel.</p><p><strong>Methods: </strong>Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating <i>PTEN</i> variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency.</p><p><strong>Results: </strong>This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance.</p><p><strong>Conclusion: </strong>This report proposes a revision of the current <i>PTEN</i> variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of <i>PTEN</i> is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss-of-function variants in <i>JPH1</i> cause congenital myopathy with prominent facial and ocular involvement.","authors":"Mridul Johari, Ana Topf, Chiara Folland, Jennifer Duff, Lein Dofash, Pilar Marti, Thomas Robertson, Juan Vilchez, Anita Cairns, Elizabeth Harris, Chiara Marini-Bettolo, Khalid Hundallah, Amal M Alhashem, Mohammed Al-Owain, Reza Maroofian, Gianina Ravenscroft, Volker Straub","doi":"10.1136/jmg-2024-109970","DOIUrl":"10.1136/jmg-2024-109970","url":null,"abstract":"<p><strong>Background: </strong>Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca²⁺ homeostasis can contribute to disease pathology.</p><p><strong>Methods: </strong>We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples.</p><p><strong>Results: </strong>The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum.DNA sequencing identified four unique homozygous loss-of-function variants in <i>JPH1</i>, encoding junctophilin-1 in the four families; one stop-gain (c.354C>A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs*30, c.1738delC;p.Leu580Trpfs*16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of <i>JPH1</i> in the F3 proband.</p><p><strong>Conclusions: </strong>Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of <i>JPH1</i> results in a congenital myopathy with prominent facial, bulbar and ocular involvement.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"992-998"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel truncating germline variant reinforces <i>TINF2</i> as a susceptibility gene for familial non-medullary thyroid cancer.","authors":"Josep Oriola, Orland Díez, Mireia Mora, Irene Halperin, Sandra Martínez, Miriam Masas, Anna Tenes, Anna Bernal, Rafael Duran, Aida Orois","doi":"10.1136/jmg-2024-110185","DOIUrl":"10.1136/jmg-2024-110185","url":null,"abstract":"<p><strong>Background: </strong>It has long been observed that there are families in which non-medullary thyroid cancer (NMTC) occurs, but few syndromes and genes have been described to date. Proteins in the shelterin complex have been implied in cancer. Here, we have studied shelterin genes in families affected by NMTC (FNMTC).</p><p><strong>Methods: </strong>We performed whole-exome sequencing (WES) in 10 affected individuals from four families with at least three affected members. Polymerase chain reaction (PCR) and Sanger sequencing were performed to search for variants in the <i>TINF2</i> gene in 40 FNMTC families. TINF2 transcripts and loss of heterozygosity (LOH) were studied in several affected patients of one family.</p><p><strong>Results: </strong>We found the c.507G>T variant in heterozygosis in the <i>TINF2</i> gene in one family, co-segregating in all five affected members. This variant affects the normal splicing. LOH was not observed.</p><p><strong>Conclusions: </strong>Our results reinforce the <i>TINF2</i> gene as a susceptibility cause of FNMTC suggesting the importance of location of frameshift variants in <i>TINF2</i>. According to our data and previous literature, <i>TINF2</i> pathogenic variants appear to be a significant risk factor for the development of NMTC and/or melanoma.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"939-942"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics of prostate cancer: a review of latest evidence.","authors":"Rose Hall, Elizabeth Bancroft, Nora Pashayan, Zsofia Kote-Jarai, Rosalind A Eeles","doi":"10.1136/jmg-2024-109845","DOIUrl":"10.1136/jmg-2024-109845","url":null,"abstract":"<p><p>Prostate cancer (PrCa) is a largely heritable and polygenic disease. It is the most common cancer in people with prostates (PwPs) in Europe and the USA, including in PwPs of African descent. In the UK in 2020, 52% of all cancers were diagnosed at stage I or II. The National Health Service (NHS) long-term plan is to increase this to 75% by 2028, to reduce absolute incidence of late-stage disease. In the absence of a UK PrCa screening programme, we should explore how to identify those at increased risk of clinically significant PrCa.Incorporating genomics into the PrCa screening, diagnostic and treatment pathway has huge potential for transforming patient care. Genomics can increase efficiency of PrCa screening by focusing on those with genetic predisposition to cancer-which when combined with risk factors such as age and ethnicity, can be used for risk stratification in risk-based screening (RBS) programmes. The goal of RBS is to facilitate early diagnosis of clinically significant PrCa and reduce overdiagnosis/overtreatment in those unlikely to experience PrCa-related symptoms in their lifetime. Genetic testing can guide PrCa management, by identifying those at risk of lethal PrCa and enabling access to novel targeted therapies.PrCa is curable if diagnosed below stage III when most people do not experience symptoms. RBS using genetic profiling could be key here if we could show better survival outcomes (or reduction in cancer-specific mortality accounting for lead-time bias), in addition to more cost efficiency than age-based screening alone. Furthermore, PrCa outcomes in underserved communities could be optimised if genetic testing was accessible, minimising health disparities.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"915-926"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}