Journal of Medical Genetics最新文献

{"title":"Foecal incontinence disorders in Wolfram syndrome: a new manifestation.","authors":"Christophe Orssaud","doi":"10.1136/jmg-2024-110233","DOIUrl":"10.1136/jmg-2024-110233","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824248","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":"Validation of the NCCN/Yale criteria for the identification of <i>CDH1</i> pathogenic variant carriers.","authors":"Benjamin A Lerner, Mar Giner-Calabuig, Cassidy Carraway, Marcy Richardson, Karl Krahn, Lisa Susswein, Sarah M Nielsen, Rachid Karam, Rosa M Xicola, Xavier Llor","doi":"10.1136/jmg-2024-110446","DOIUrl":"10.1136/jmg-2024-110446","url":null,"abstract":"<p><strong>Background: </strong>Diffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in <i>CDH1</i>. We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for <i>CDH1</i> PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of <i>CDH1</i> PV carriers.</p><p><strong>Methods: </strong>We aggregated demographic and clinical data of all <i>CDH1</i> PV carriers identified at three US commercial laboratories. These data were used to calculate the sensitivity of the IGCLC, LBC-expanded and National Comprehensive Cancer Network (NCCN)/Yale criteria.</p><p><strong>Results: </strong>Data on 708 probands and their 4318 family members were included in the analysis. In this cohort, the sensitivities for detecting <i>CDH1</i> PVs were 23.6% for IGCLC criteria, 35.7% for LBC-expanded criteria and 82.2% for NCCN/Yale criteria.</p><p><strong>Conclusion: </strong>In a large cohort of <i>CDH1</i> PV carriers to date, the IGCLC and LBC-expanded criteria called for genetic testing in a minority of <i>CDH1</i> PV carriers while the Yale criteria detected the large majority. Along with their superior sensitivity, the NCCN/Yale criteria address critical practical challenges in cancer genetics by not depending heavily on pathology information from family members which is often lacking and by incorporating recommendations from other cancer genetics guidelines.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824250","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":"Unveiling non-coding <i>DMD</i> variants: synergising RNA sequencing and DNA sequencing for enhanced molecular diagnosis.","authors":"Yinghong Pan, Babi Ramesh Reddy Nallamilli, Ruby Liu, Naga Guruju, Daniel Lesperance, Zeqiang Ma, Abhinav Mathur, Kayla Banks, Ann S Martin, Rolando García, Fen Guo, Madhuri Hegde","doi":"10.1136/jmg-2024-110152","DOIUrl":"10.1136/jmg-2024-110152","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in the <i>DMD</i> gene are associated with dystrophinopathy including Duchenne and Becker muscular dystrophy (DMD/BMD). Targeted <i>DMD</i> gene, gene panels, exomes and genome sequencing have advanced genetic diagnostics, yet some cases remain elusive.</p><p><strong>Methods: </strong>We performed total RNA sequencing (RNAseq) on muscle biopsy from 13 male patients with a clinical diagnosis of DMD/BMD. Splice aberration events are evaluated using the Integrative Genomics Viewers. Targeted DNA sequencing result was used/re-analysed to confirm complex rearrangement events identified.</p><p><strong>Results: </strong>RNAseq identified aberration splicing or expression events in the <i>DMD</i> gene of 12 cases. Splice-altering intronic single nucleotide variant events including c.7309+5G>T, c.7309+5G>A, c.3276+1G>A and c.3603+820G>T were identified in four cases. Splice-altering events were also detected in one case with small indel c.94-38_94del and two cases with intragenic deletions (exons 51-52 and 45-47 deletions). Furthermore, complex DNA rearrangements inducing aberration splicing/expression events were identified in five cases involving exons 44-45, 55-56, 2-79, 45-79 or 68-79, which were concordant with their DNA sequencing reanalysis results. Some cases with exon deletions have presented non-canonical transcripts expression. The RNAseq result showing aberrant splicing/expression in different exon regions in most of these cases corresponded with their immunohistochemical dystrophin staining results and/or clinical symptoms.</p><p><strong>Conclusion: </strong>Our data demonstrated RNAseq is a powerful tool to provide functional data for <i>DMD</i> splice aberration events, especially when integrating with immunohistochemical testing and DNA sequencing, for elucidating the pathogenicity of <i>DMD</i> variants and achieving a precise genetic diagnosis in patients with DMD/BMD clinical presentation but without definitive diagnoses after routine genetic testing.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813003","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":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","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":"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":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-09","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":"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":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-09","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":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Portraying the full picture of Neurofibromatosis-Noonan syndrome: a systematic review of literature.","authors":"Omeyma Trimeche, Rania Sakka, Ekram Hajji, Abdelmouhaymen Missaoui, Bilel Ben Amor, Ines Bayar, Sana Abid, Hela Marmouch, Hanen Sayedi, Ines Khochtali","doi":"10.1136/jmg-2024-110253","DOIUrl":"10.1136/jmg-2024-110253","url":null,"abstract":"<p><strong>Background and aims: </strong>Neurofibromatosis-Noonan syndrome (NFNS) is an extremely rare genetic entity combining the clinical phenotype of two conditions: neurofibromatosis type 1 syndrome (NF1) and Noonan syndrome (NS). Nevertheless, many inconsistencies reside in our understanding of this condition, mainly its clinical features and genetic background. Through this systematic review, we aim to shed light on the epidemiological features, the broad clinical spectrum, the underlying genetic defects and the associated comorbidities of NFNS.</p><p><strong>Methods: </strong>Medline, Scopus and Google Scholar were searched for publications on the clinical and genetic features of patients with NFNS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and the study protocol was registered in PROSPERO.</p><p><strong>Results: </strong>Of 951 records screened, 42 were eligible. The mean age at diagnosis was 14.7 years ranging from 0 to 69 years. As for the circumstance of discovery of NFNS, it was dominated by family investigation followed by neurofibromas, facial dysmorphia and short stature (SS). Prematurity was noted in 40.9% of cases. The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines. Macrocephaly, scoliosis and cardiopathies occurred in 26%, 42.4% and 36.9% of cases, respectively. Tumours were found in 18.4% of cases. As for the genetic foundation of NFNS, <i>NF1</i> gene mutations were depicted in 87.5% of individuals.</p><p><strong>Conclusions: </strong>Based on our findings, we emphasise on the importance of searching for NS features in patients with NF1 since the prognosis, comorbidities and consequently management could be altered.</p><p><strong>Prospero registration number: </strong>42024522238.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791739","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}