Journal of Medical Genetics最新文献

{"title":"Impact of NICE Guideline NG241 'Ovarian Cancer: identifying and managing familial and genetic risk' on a regional NHS family history and clinical genetics service.","authors":"Alexander Roe, Andrea Forman, Fiona Lalloo, Terri P McVeigh, Helen Hanson, Katie Snape","doi":"10.1136/jmg-2024-110481","DOIUrl":"10.1136/jmg-2024-110481","url":null,"abstract":"<p><strong>Background: </strong>NICE Guideline NG241: identifying and managing familial and genetic risk of ovarian cancer (OC) was published by the National Institute for Health and Care Excellence (NICE) in March 2024. NG241 advises germline genetic testing of genes predisposing to OC in unaffected individuals with an OC family history at different mutation likelihood thresholds depending on age and sex, ranging from 2% to 10% likelihood of finding a germline pathogenic variant (GPV). Prior to implementation of NG241, updates to the NHS England National Genomic Test Directory would be required. Clinical genetics services have to consider equity of access to assessment and testing across all familial cancer types, best use of their limited resources and other factors such as complexity of delivery of clinical pathways.</p><p><strong>Methods: </strong>We analysed data from 8011 patients who provided digital family histories to the South West Thames Centre for Genomics between October 2019 and June 2024.</p><p><strong>Results: </strong>We estimate 527/782 (68%) females and 28/77 (36%) males would meet test criteria for NICE NG241. We estimate we would reject 2919/5485 (53%) females and 135/1208 (11%) males with the same likelihood of carrying a GPV, but with a breast cancer rather than OC family history. Testing the familial OC cohort at a universal 5% threshold in OC families would detect ~11 carriers for 229 tests compared with ~8 carriers for 278 tests following NG241 criteria.</p><p><strong>Conclusion: </strong>Our data highlight additional factors needing to be considered before the NICE Guideline NG241 can be implemented by regional genetics services.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458222","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":"Gene prioritisation for enhancing molecular diagnosis in rare skeletal muscle disease cohort.","authors":"Victoria Lillback, Gaber Bergant, Maria Francesca Di Feo, Ivana Babić Bozović, Annalaura Torella, Mridul Johari, Aleš Maver, Katarina Pelin, Filippo M M Santorelli, Vincenzo Nigro, Peter Hackman, Borut Peterlin, Bjarne Udd, Marco Savarese","doi":"10.1136/jmg-2024-110212","DOIUrl":"https://doi.org/10.1136/jmg-2024-110212","url":null,"abstract":"<p><strong>Background: </strong>Inherited rare skeletal muscle diseases cause muscle weakness and wasting of variable severity. Without a molecular diagnosis, patients often endure prolonged diagnostic journeys, leading to delays in appropriate management of the disease. This occurs in approximately 60% of patients with rare diseases.</p><p><strong>Methods: </strong>To facilitate reanalysis of 278 unsolved patients, we used a gene prioritisation tool Exomiser, which standardises analysis by ranking causative variants based on phenotype relevance and variant pathogenicity. Before analysis, we benchmarked Exomiser for variant prioritisation with solved cases and for novel disease gene discovery with mock cases with variants in candidate disease genes. Additionally, we studied the significance of the specificity of the phenotype descriptions.</p><p><strong>Results: </strong>In our study, Exomiser ranked genes in the top 10 correctly in 97.4% of controls with previously detected causative variants. Moreover, 57.1% of candidate genes in mock cases were similarly prioritised in the top 10. We also showed that three parental muscle disease human phenotype ontologies describing the patient phenotype performed as well as patient-specific ones, with a p value of 0.68 for difference in performance. The provided automation and standardisation of variant interpretation resulted in two novel diagnoses and in findings, either in known muscle disease genes or in novel candidate genes, which need further investigation.</p><p><strong>Conclusions: </strong>Exomiser is recommended for initial and periodic reanalyses of exomes in unsolved patients with myopathy, as it benefits from literature updates and minimises effort. This approach could also extend to whole genome sequencing data, aiding the interpretation of variants beyond coding regions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566586","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":"Outcomes and experiences of genetic testing in children with congenital heart disease.","authors":"Ansley M Morrish, Bridget R O'Malley, Desiree C K Hilton, Annabel E Webb, Bruce Bennetts, Gary F Sholler, Janine Smith, Gillian M Blue","doi":"10.1136/jmg-2024-110553","DOIUrl":"https://doi.org/10.1136/jmg-2024-110553","url":null,"abstract":"<p><strong>Background: </strong>Following genomic advances, genetic testing options for paediatric patients with congenital heart disease (CHD) have evolved significantly. A single-site audit was conducted to assess testing outcomes and a survey created to explore family experiences and preferences.</p><p><strong>Method: </strong>All genetic tests ordered in postcardiac surgery patients with CHD at The Children's Hospital at Westmead between January 2017 and December 2021 were reviewed. Diagnostic yield, clinical and demographic factors, and testing trends over time were evaluated. Surveys were sent to parents of children who had met a clinical geneticist (n=112).</p><p><strong>Results: </strong>Genetic testing was completed in 607 individuals (74 molecular testing; 533 cytogenetic testing only). The diagnostic rate was 36% and 9%, respectively. Use of molecular testing significantly increased over time (p=0.033), but yield did not (p=0.288). Molecular testing yield was high in neonates (64%), and patients with extracardiac anomalies (40%) or relevant family history (40%). Brain (p=0.022), haematological/cancer (p≤0.001), immune (p≤0.001), endocrine (p≤0.001) anomalies and intellectual disability (p=0.027) were associated with a diagnosis following cytogenetic testing. Short stature was significantly associated with diagnostic yield following molecular testing (p=0.012). Survey respondents (n=28) reported a positive experience (p=0.013) with minimal decisional regret (p=0.322).</p><p><strong>Conclusion: </strong>Cytogenetic testing remains an important first-tier test in CHD. Furthermore, molecular testing guided by a clinical geneticist generates a high rate of genetic diagnoses. Parents of children with CHD value genetic testing with little regret.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515913","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":"Response to: 'Commentary on Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank' by Møller <i>et al</i>.","authors":"Joaquín Castillo-Iturra, Ariadna Sánchez, Leticia Moreira, Maria Pellisé, Francesc Balaguer","doi":"10.1136/jmg-2024-110468","DOIUrl":"10.1136/jmg-2024-110468","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"151"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950245","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":"Homozygous missense variant in <i>C2orf69</i> causes early-onset neurodegeneration, leukoencephalopathy and autoinflammation.","authors":"Rachel Youjin Oh, Michael Maier, Susan Blaser, Jessie Cameron, Cynthia Hawkins, Bruno Reversade, Grace Yoon","doi":"10.1136/jmg-2024-110419","DOIUrl":"10.1136/jmg-2024-110419","url":null,"abstract":"<p><p>Biallelic pathogenic variants in <i>C2orf69</i> cause a fatal autosomal recessive multisystem disorder characterized by recurrent autoinflammation, hypomyelination, progressive neurodegeneration, microcephaly, failure to thrive, liver dysfunction, respiratory chain defects and accumulation of glycogen in skeletal muscle. No missense variants in <i>C2orf69</i> have been reported to date.We report a 6-year-old boy with microcephaly, global developmental delays, lower limb spasticity with hyperreflexia, epilepsy, abnormal brain MRI, failure to thrive, recurrent fevers and transaminitis. Whole-exome sequencing identified a homozygous missense c.320 C>G, p.(Pro107Arg) variant of uncertain significance (VUS) in <i>C2orf69</i> Skeletal muscle biopsy showed active and chronic muscle fibre degeneration with deposits of periodic acid-Schiff-positive material in affected tissues, consistent with abnormal glycogen storage. Mitochondrial respiratory assays were normal in muscle tissue. Primary patient fibroblasts showed normal levels of mRNA expression but significantly reduced levels of endogenous C2ORF69 protein and GBE1 by Western blot. We report a patient with a homozygous missense variant in <i>C2orf69</i>, causing loss of function. Depletion of endogenous GBE1 in affected cells can be considered a biomarker for this disorder and assist in the interpretation of VUS in <i>C2orf69</i> This expands the clinical and genetic spectrum of <i>C2orf69</i>-related disorder.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"206-209"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029005","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":"Sexual dimorphism in <i>SMAD3</i> pathogenic variant-harbouring individuals.","authors":"Julie Richer, Joe Davis Velchev, Sharan Goobie, Christie A Boswell-Patterson, Ingrid M B H van de Laar, Judith M A Verhagen, Marja W Wessels, Jolien W Roos-Hesselink, Ilse Luyckx, Hussein Al-Amodi, Michael W A Chu, Anne-Marie Laberge, Bekim Sadikovic, Tugce Balci, Aline Verstraeten, Bart Loeys","doi":"10.1136/jmg-2024-110219","DOIUrl":"10.1136/jmg-2024-110219","url":null,"abstract":"<p><strong>Background: </strong>Individuals harbouring <i>SMAD3</i> pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in <i>SMAD3-</i>variant-harbouring patients.</p><p><strong>Methods: </strong>We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in <i>SMAD3</i>. We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 <i>SMAD3</i> patients reported in the literature between 2011 and 2023.</p><p><strong>Results: </strong>In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028).</p><p><strong>Conclusions: </strong>Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"199-205"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921909","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":"Robust detection of pathogenic <i>HYDIN</i> variants that cause primary ciliary dyskinesia using RNA-seq of nasal mucosa.","authors":"Minako Hijikata, Kozo Morimoto, Masashi Ito, Keiko Wakabayashi, Akiko Miyabayashi, Naoto Keicho","doi":"10.1136/jmg-2024-110400","DOIUrl":"10.1136/jmg-2024-110400","url":null,"abstract":"<p><p>Primary ciliary dyskinesia (PCD, OMIM 244400) is a rare genetic disorder that affects motile cilia and is characterised by impaired mucociliary clearance of the airway epithelium, which results in chronic upper and lower airway infections. While short-read next-generation sequencing technology has been used for the genetic testing of PCD, its effectiveness is limited in identifying variants in the <i>HYDIN</i> gene because of the nearly identical pseudogene <i>HYDIN2</i> As we confirmed that the <i>HYDIN2</i> gene was not expressed in airway cells, we obtained nasal mucosa biopsy specimens for total RNA sequencing (RNA-seq) with library enrichment using exome oligos. Among the 34 nasal samples from patients suspected of having PCD, three aberrant splicing patterns in <i>HYDIN</i> were identified in two samples. Variant calls from RNA-seq combined with long-read amplicon sequencing of genomic DNA detected four pathogenic variants exclusively in the <i>HYDIN</i> gene. Therefore, RNA-seq in combination with long-read sequencing significantly facilitates the accurate genetic diagnosis of PCD caused by <i>HYDIN</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"180-184"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978950","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":"Advances in research on the mechanism of tsRNA action in tumours.","authors":"Yan Gao, Yanzhao Huang, Kaiyun Guo, Jun Cheng, Yuting Luo, Yi Deng, Ming Lei","doi":"10.1136/jmg-2024-110437","DOIUrl":"10.1136/jmg-2024-110437","url":null,"abstract":"<p><p>tsRNA is a class of non-coding RNAs derived from mature or precursor tRNAs. In recent years, more and more studies have explored the correlation between tsRNAs and tumours. tsRNAs can affect the biological behaviours of tumour cells such as proliferation, apoptosis and metastasis by regulating gene expression, protein translation or post-transcriptional regulation. In this paper, we systematically review the production, biological function and research progress of tsRNA in tumour and discuss its prospects as biomarkers and therapeutic targets.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"152-159"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909688","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":"Clonazepam repurposing in <i>ARID1B</i> patients through conventional RCT and N-of-1 trials: an experimental strategy for orphan disease development.","authors":"Pleuntje J van der Sluijs, Koshar Safai Pour, Cécile L Berends, Matthijs D Kruizinga, Annelieke R Müller, Agnies M van Eeghen, Mar Rodríguez-Girondo, Maria J Juachon, Duco Steenbeek, Adam F Cohen, Rob G J A Zuiker, Gijs W E Santen","doi":"10.1136/jmg-2024-109951","DOIUrl":"10.1136/jmg-2024-109951","url":null,"abstract":"<p><strong>Background: </strong>Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in <i>ARID1B</i> patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.</p><p><strong>Methods: </strong>This study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, <i>ARID1B</i> patients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks).</p><p><strong>Results: </strong>In the clonazepam group (<i>n</i>=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed 'no change' after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (<i>n</i>=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient.</p><p><strong>Conclusions: </strong>Our approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in <i>ARID1B</i> patients.</p><p><strong>Trial registration number: </strong>EUCTR2019-003558-98, ISRCTN11225608.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"210-218"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909689","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":"Reassessment and reclassification of variants of unknown significance in patients with cardiomyopathy in a specialist department.","authors":"Sinead Horgan, Huafrin Kotwal, Antonetta Malan, Neha Sekhri, Luis R Lopes","doi":"10.1136/jmg-2024-110208","DOIUrl":"10.1136/jmg-2024-110208","url":null,"abstract":"<p><strong>Background: </strong>The utility of diagnostic genetic testing in cardiomyopathy has grown significantly, due to the discovery of novel genes and greater awareness among healthcare professionals. However, a substantial proportion of cases (around 50%) yield no causative genetic variants or have variants of unknown significance (VUS), limiting their use in clinical management and familial screening. The increase in data quantity and quality in reference databases, coupled with variant interpretation guidelines, allows for periodic reanalysis of VUS, potentially reducing diagnostic gaps.</p><p><strong>Methods: </strong>This study presents a review of VUS results identified in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) probands over a 5-year period, using American College of Medical Genetics and Genomics criteria. A total of 248 VUS from 233 reports were reviewed, with the majority of patients with a diagnosis of HCM (n=112), followed by DCM (n=99) and ACM (n=22).</p><p><strong>Results: </strong>Four (1.6%) VUS showed sufficient evidence to upgrade to likely pathogenic/pathogenic status, while 8 (3.2%) were downgraded to benign. The majority 236 (95.2%) remained VUS after reanalysis, of which 12 (4.7%) had potential to reclassification to benign or likely pathogenic/pathogenic depending on further data.</p><p><strong>Conclusion: </strong>The study emphasises the importance of periodic re-evaluation of VUS results for clinical management of probands as well as cascade testing. We show feasibility of conducting reclassification analysis in a referral centre, but highlight the need for ongoing collaboration between clinical and laboratory experts. Our work supports the current recommendation of reclassification every 3-5 years to keep pace with evolving evidence.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"185-190"},"PeriodicalIF":3.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853438","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}