Journal of Medical Genetics最新文献

{"title":"The NHS England Jewish BRCA Testing Programme: overview after first year of implementation (2023-2024).","authors":"Bethany Torr, Nicola Bell, Ruth McCarthy, Monica Hamill, Joshua Nolan, Sudeekshna Muralidharan, Charlotte Andrews, Mikel Valganon-Petrizan, Yasmin Clinch, Suzanne MacMahon, Alison Morilla, Angela George, Paul Ryves, Pooja Dasani, Moses Adegoroye, Helene Schlecht, George J Burghel, Wendy Ornadel, Nicole Gordon, Lisa Steele, Susana Lukic, Emily Watts, D Gareth Evans, Ranjit Manchanda, Clare Turnbull","doi":"10.1136/jmg-2024-110390","DOIUrl":"10.1136/jmg-2024-110390","url":null,"abstract":"<p><strong>Background: </strong>The NHS Jewish BRCA Testing Programme is offering germline <i>BRCA1</i> and <i>BRCA2</i> genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research.</p><p><strong>Methods: </strong>We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023-January 2024) and their families to observe trends in uptake and outcomes of testing.</p><p><strong>Results: </strong>Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder).Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively).</p><p><strong>Conclusion: </strong>Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"69-73"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881802","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":"Six at Sixty. 'Have you tested for 22q?'","authors":"Peter Scambler","doi":"10.1136/jmg-2024-110504","DOIUrl":"10.1136/jmg-2024-110504","url":null,"abstract":"<p><p>In 1997, the <i>Journal of Medical Genetics</i> published our paper on the spectrum of clinical features associated with interstitial chromosome 22q11 deletions. This copy number variation is associated with an extraordinary range of clinical features, which led initially to its association with several diagnostic labels. Since 1997 work on clinical and basic science aspects of the syndrome and the genes reduced to hemizygosity have provided a wealth of information pertaining to both best practice care and underlying biology. It is recognised that 22q11.2 deletion syndrome is an excellent model for probing mechanisms underlying psychiatric disease, cardiovascular development and much more.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"147-149"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006694","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":"Tumour spectrum in <i>AKT1</i>-related Proteus syndrome: a systematic review of clinical reports and series.","authors":"Olivia M Rostagni, Charlotte Lr Early, Mia B Hodges, Justice O Obasohan, Julie C Sapp, Alicia A Livinski, Leslie G Biesecker, Christopher A Ours","doi":"10.1136/jmg-2024-110173","DOIUrl":"10.1136/jmg-2024-110173","url":null,"abstract":"<p><p><i>AKT1</i>-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition. We conducted a systematic review to determine the range and characteristics of these tumours. A systematic review was conducted to identify clinical reports and clinical series of Proteus syndrome published between 1983 and 2023. Affected individuals were selected based on existing Proteus syndrome diagnostic criteria and expert review. Six databases were searched, and each unique record was screened independently by two authors. Two authors extracted the following data from each included report per individual: demographics, tumour diagnosis, characteristics, outcome, clinical features of Proteus syndrome and report of <i>AKT1</i> genetic testing. The literature searches yielded 3074 records of which 1239 were unique and screened. After screening, 190 records were included. These represented 205 unique individuals with Proteus syndrome. There were 38 individuals (19%) with at least one tumour diagnosis. The average age of tumour diagnosis was 15.1 years (SD 12.1). The most frequent tumour sites were genitourinary/gynaecologic (25 tumours, 53%) followed by the central nervous system (11 tumours, 23%). Most tumours were benign and treated with surgery alone. This systematic review provides a summary of Proteus syndrome-associated tumours from the literature. These data assist clinicians in the diagnosis and prognosis of these tumours. The study highlights the knowledge gap of possible adult-onset tumours and long-term outcomes, which requires further research. <b>PROSPERO registration number</b> CRD42021237914.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"74-81"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791698","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":"Genomic sequencing in paediatric oncology: navigating conflicting roles and responsibilities.","authors":"Catherine Goudie, Ma'n H Zawati, Bartha Maria Knoppers, Anne-Marie Laberge","doi":"10.1136/jmg-2024-110410","DOIUrl":"10.1136/jmg-2024-110410","url":null,"abstract":"<p><strong>Background: </strong>This study explores the ethical and moral challenges faced by paediatric oncologists when they are informed of patient genomic results, particularly during molecular tumour boards (MTBs), highlighting the interplay between their clinic, research and expert roles.</p><p><strong>Methods: </strong>This was an explanatory sequential mixed-methods study using a survey distributed to paediatric oncologists in Quebec followed by optional semi-structured interviews. Oncologists' attitudes and comfort levels with six hypothetical germline DNA results identified in a patient from a clinical vignette were assessed using Likert scales. Hypothetical genetic results represented ethical challenges of extended paediatric genomic sequencing. Interviews were conducted with a subgroup of participants to gain insight and context on key survey results.</p><p><strong>Results: </strong>Eighty per cent (n=28) of oncologists in Quebec completed the survey; five participated in the interviews. Comfort levels of oncologists were influenced by the type of genetic result (expected, secondary, incidental finding), whether or not the oncologist was the patient's treating physician, and whether the information disclosed to the patient aligned with the information that they had received. Awareness of a genetic result was sufficient to trigger a feeling of responsibility and liability for that result.</p><p><strong>Conclusion: </strong>Oncologists who take part in genomic sequencing initiatives and who attend MTBs have privileged access to genomic results, above what may be accessible to patients. This imbalance in knowledge contributes to moral discomfort experienced by oncologists who feel responsible for genomic information they are aware of. We propose recommendations applicable to consent processes, policies and pipelines for sharing genomic results.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"138-146"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801131","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>KIF21A</i>-associated peripheral neuropathy defined by impaired binding with TUBB3.","authors":"Nicholas A Borja, Mohammad Faraz Zafeer, Stephanie Bivona, LéShon Peart, Sakir Humayun Gultekin, Guney Bademci, Mustafa Tekin","doi":"10.1136/jmg-2024-109908","DOIUrl":"10.1136/jmg-2024-109908","url":null,"abstract":"<p><p><i>KIF21A</i> encodes a kinesin motor protein associated with isolated congenital fibrosis of the extraocular muscles (CFEOM), which occurs when the autoinhibitory interaction between its motor and third coiled-coil domains is disrupted. In this study, we describe a female child who is heterozygous for a novel de novo missense variant in <i>KIF21A</i> p.Leu664Pro, located in the second coiled-coil domain that was absent in her unaffected parents and in healthy population cohorts. She presented with progressive peripheral neuropathy, hypoplasia of the corpus callosum and strabismus in the absence of CFEOM. Protein modelling predicts that the KIF21A variant leads to significant alterations in its structure as well as binding with TUBB3. Co-immunoprecipitation data was consistent with decreased binding of KIF21A p.Leu664Pro to TUBB3 in vitro compared with reference. Taken together, we delineate a <i>KIF21A</i>-related phenotype defined by progressive peripheral neuropathy, brain anomalies, developmental delay and comitant strabismus potentially stemming from the disruption of the interaction between KIF21A and TUBB3.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"117-122"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791592","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":"Predicting the likelihood of <i>BRCA1/2</i> germline pathogenic variants in unselected patients with breast cancer: analysis of more than 10,000 individuals.","authors":"Jie Sun, Lu Yao, Jiuan Chen, Li Hu, Juan Zhang, Ye Xu, Yuntao Xie","doi":"10.1136/jmg-2024-110332","DOIUrl":"10.1136/jmg-2024-110332","url":null,"abstract":"<p><strong>Background: </strong>Models for accurately predicting the likelihood of <i>BRCA1/2</i> germline pathogenic variants (PVs) based on a large cohort of unselected patients with breast cancer are limited.</p><p><strong>Methods: </strong>A logistic regression model to predict the <i>BRCA1/2</i> carrier probability, named PKCBRCA, was established and validated based on 10 167 unselected Chinese patients with breast cancer treated in Peking University Cancer Hospital between October 2003 and August 2020. All patients were tested for <i>BRCA1/2</i> germline variants. The discrimination and calibration of the model were assessed.</p><p><strong>Results: </strong>A total of 601 (5.9%) patients carried <i>BRCA1/2</i> germline PVs in the entire cohort of 10 167 unselected patients with breast cancer. The cohort was separated into a training set (n=6331; 387 (6.1%) <i>BRCA1/2</i> carriers) and a validation set (n=3836; 214 (5.6%) <i>BRCA1/2</i> carriers). Five variables strongly associated with <i>BRCA1/2</i> carrier probability were incorporated in the establishment of PKCBRCA including age of diagnosis, bilateral breast cancer, family history of breast or ovarian cancer, hormone receptor and ERBB2. PKCBRCA showed a good ability to discriminate both in the training set (area under the receiver operating characteristic curve (AUC)=0.77) and in the validation set (AUC=0.77).</p><p><strong>Conclusion: </strong>Our model provides a useful tool for accurately assessing the <i>BRCA1/2</i> carrier probability for unselected patients with breast cancer.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"62-68"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812984","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":"Aortic and arterial manifestations and clinical features in <i>TGFB3</i>-related heritable thoracic aortic disease: results from the Montalcino Aortic Consortium.","authors":"Michelle Su-Anne Lim, Dong-Chuan Guo, Walter Velasco Torrez, Andrew Lai, Jonathan Schweber, Nikita Garg, Julie Fleischer, Catherine Boileau, Julie De Backer, Artur Evangelista, Guillaume Jondeau, Carine Le Goff, Olivier Milleron, Laura Muiño-Mosquera, Shaine Morris, Maral Ouzounian, Elena Cervi, Julien Marcadier, Anthony Caffarelli, Sherene Shalhub, Reed Pyeritz, Angela Yetman, Dianna Milewicz, Alan C Braverman","doi":"10.1136/jmg-2024-110251","DOIUrl":"10.1136/jmg-2024-110251","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in <i>TGFB3</i> may lead to a syndromic genetic aortopathy. Heritable thoracic aortic disease (HTAD) and arterial events may occur in <i>TGFB3</i>-related disease but there are limited outcomes data on vascular events in this condition.</p><p><strong>Methods: </strong>Clinical data, phenotypical features and aortic outcomes in individuals with pathogenic/likely pathogenic (P/LP) <i>TGFB3</i> variants enrolled in the Montalcino Aortic Consortium registry were reviewed.</p><p><strong>Results: </strong>34 individuals (56% male, median age 42 years, IQR 17-49, range 3-74 years) with P/LP <i>TGFB3</i> variants were studied. Craniofacial, cutaneous and musculoskeletal features seen in Loeys-Dietz syndrome were variably present. Extra-aortic cardiovascular features included arterial tortuosity (25%), extra-aortic arterial aneurysms (6%) and mitral valve prolapse (21%).Aortic dilation (Z-Score>2) was present in 10 individuals (29%) and aortic dissection occurred in 2 (6%). Type A aortic dissection occurred in two patients (aged between 55 years and 60 years), and one of these patients experienced a type B aortic dissection 6 years later. Seven adults (median age 62 years, range 32-69 years) with aortic root dilation (41-49 mm) are being followed. No patients have undergone prophylactic aortic surgery. Twenty-five per cent of children have aortic dilation. Sixty-eight per cent of the entire cohort remains free of aortic disease. No deaths have occurred.</p><p><strong>Conclusions: </strong><i>TGFB3</i>-related HTAD is characterised by late-onset and less penetrant thoracic aortic and arterial disease compared with other transforming growth factor β HTAD. Based on our data, a larger aortic size threshold for prophylactic aortic surgery is appropriate in patients with <i>TGFB3</i>-related HTAD compared with HTAD due to <i>TGFBR1</i> or <i>TGFBR2</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"82-88"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801128","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":"Retrospective study on the utility of optical genome mapping as a follow-up method in genetic diagnostics.","authors":"Paul Dremsek, Anna Schachner, Theresa Reischer, Elisabeth Krampl-Bettelheim, Dieter Bettelheim, Sybille Vrabel, Zoja Delissen, Mateja Pfeifer, Beatrix Weil, Robert Bajtela, Markus Hengstschläger, Franco Laccone, Jürgen Neesen","doi":"10.1136/jmg-2024-110265","DOIUrl":"10.1136/jmg-2024-110265","url":null,"abstract":"<p><strong>Background: </strong>Current standard-of-care (SOC) methods for genetic testing are capable of resolving deletions and sequence variants, but they mostly fail to provide information on the breakpoints of duplications and balanced structural variants (SV). However, this information may be necessary for their clinical assessment, especially if the carrier's phenotype is difficult to assess and/or carrier analysis of relatives is not viable. A promising approach to solving such challenging cases arises with access to optical genome mapping (OGM) but has not been systematically explored as of yet.</p><p><strong>Methods: </strong>In this retrospective study, we evaluated diagnostic cases from a 1-year period (2023) in which an SV discovery by SOC methods (microarray, karyotyping and whole-exome sequencing) was followed up by OGM, with the objective to unlock clinically relevant information about the SV.</p><p><strong>Results: </strong>Seven cases were shown by SOC methods to bear potential pathogenic SVs and were consequently followed up by OGM. Of these, six were solved by the additional use of OGM alone. One case required sequencing after OGM analysis to further specify the SV's breakpoints. In all seven cases, OGM was crucial for determining the clinical relevance of the detected SV.</p><p><strong>Conclusion: </strong>This study describes the use of OGM as a valuable method for characterising duplications and balanced SVs. Often, this additional information does not add to the quality of a clinical report. However, for a subset of patients, these data are critical, especially in the prenatal setting or when no familial analyses are possible.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"89-96"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801133","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":"Hiding in plain sight: a partial deletion of <i>BRCA1</i> exon 7 undetectable by MLPA is a Nepali founder variant.","authors":"Virginia Clowes, Jenny C Taylor, Alistair T Pagnamenta","doi":"10.1136/jmg-2024-110422","DOIUrl":"10.1136/jmg-2024-110422","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"54-56"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812590","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":"A tandem duplication of exon 42 of the <i>DMD</i> gene is a likely benign variant.","authors":"Jesse B G Hayesmoore, Ruth Newbury-Ecob, Sarah Durell, Amy Dillon, Farah Kanani, Fiona Beecroft, Joanna Jarvis, Deirdre Cilliers, Carl Fratter","doi":"10.1136/jmg-2024-110159","DOIUrl":"10.1136/jmg-2024-110159","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"123-125"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881586","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}