Journal of Medical Genetics最新文献

{"title":"Protein-truncating and rare missense variants in <i>ATM</i> and <i>CHEK2</i> and associations with cancer in UK Biobank whole-exome sequence data.","authors":"Toqir K Mukhtar, Naomi Wilcox, Joe Dennis, Xin Yang, Marc Naven, Nasim Mavaddat, John R B Perry, Eugene Gardner, Douglas F Easton","doi":"10.1136/jmg-2024-110127","DOIUrl":"10.1136/jmg-2024-110127","url":null,"abstract":"<p><strong>Background: </strong>Deleterious germline variants in <i>ATM</i> and <i>CHEK2</i> have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear.</p><p><strong>Methods: </strong>Cancer associations for coding variants in <i>ATM</i> and <i>CHEK2</i> were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348 488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0.1%).</p><p><strong>Results: </strong>PTVs in <i>ATM</i> were associated with increased risks of nine cancers at p<0.001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p<0.05 (colon, diffuse non-Hodgkin's lymphoma (DNHL), rectosigmoid junction). Carriers of rMSVs had increased risks of four cancers (p<0.05: stomach, pancreas, prostate, Hodgkin's disease (HD)). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile.PTVs in <i>CHEK2</i> were associated with three cancers at p<0.001 (breast, prostate, HD) and six at p<0.05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p<0.001: breast, prostate, LL; p<0.05: melanoma, multiple myeloma).</p><p><strong>Conclusion: </strong>PTVs in <i>ATM</i> and <i>CHEK2</i> are associated with a wide range of cancers, with the highest RR for pancreatic cancer in <i>ATM</i> PTV carriers. These findings can inform genetic counselling of carriers.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"1016-1022"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108128","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":"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":"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}

{"title":"Heterozygous <i>COL17A1</i> variants are a frequent cause of amelogenesis imperfecta.","authors":"Tero T Kivelä, Walter Lisch, Jayne E Weiss","doi":"10.1136/jmg-2024-110310","DOIUrl":"10.1136/jmg-2024-110310","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"982"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108226","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":"From onset to blindness: a comprehensive analysis of <i>RPGR</i>-associated X-linked retinopathy in a large cohort in China.","authors":"Jiawen Wu, Junfeng Li, Daowei Zhang, Hongli Liu, Ting Li, Ping Xu, Yingke Zhao, Chenchen Li, Fangyuan Hu, Qian Li, Shenghai Zhang, Ji-Hong Wu","doi":"10.1136/jmg-2024-110088","DOIUrl":"10.1136/jmg-2024-110088","url":null,"abstract":"<p><strong>Background: </strong>Variants in the <i>RPGR</i> are the leading cause of X-linked retinopathies (XLRPs). Further in-depth investigation is needed to understand the natural history.</p><p><strong>Methods: </strong>Review of all case records, molecular genetic testing results, best-corrected visual acuity (BCVA), retinal imaging data (including fundus autofluorescence imaging and optical coherence tomography (OCT)), static visual field (VF) assessments and full-field electroretinogram.</p><p><strong>Results: </strong>Genetic testing was conducted on 104 male patients from 89 family pedigrees, identifying 22 novel variants and 1 de novo variant. The initial symptoms appeared in 78.2% of patients at a median age of 5 years. BCVA declined at a mean rate of 0.02 (IQR, 0-0.04) logarithm of the minimum angle of resolution per year, with a gradual, non-linear decrease over the first 40 years. Autofluorescence imaging revealed macular atrophy at a median age of 36.1 (IQR, 29.9-43.2) years. Patients experienced blindness at a median age of 42.5 (IQR, 32.9-45.2) years according to WHO visual impairment categories. OCT analysis showed a mean ellipsoid zone narrowing rate of 23.3 (IQR, -1.04-22.29) µm/month, with an accelerated reduction in the first 40 years (p<0.01). The median age at which ERG no longer detected a waveform was 26.5 (IQR, 20.5-32.8) years. Comparison by variant location indicated faster progression in patients with exon 1-14 variants during the initial two decades, while those with ORF15 variants showed accelerated progression from the third decade.</p><p><strong>Conclusions: </strong>We provide a foundation for determining the treatment window and an objective basis for evaluating the therapeutic efficacy of gene therapy for XLRP.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"973-981"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995905","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":"Germline testing for breast cancer patients in England: illogical to prioritise grade 1 breast cancer aged 30-39 over grade 3 aged 40-49 years?","authors":"D Gareth Evans, Sacha J Howell, George J Burghel, Claire Forde, Fiona Lalloo, Miriam J Smith, Anthony Howell, Ashu Gandhi, Emma Roisin Woodward","doi":"10.1136/jmg-2024-110183","DOIUrl":"10.1136/jmg-2024-110183","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"935-936"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759252","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":"The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification.","authors":"Charlie F Rowlands, Alice Garrett, Sophie Allen, Miranda Durkie, George J Burghel, Rachel Robinson, Alison Callaway, Joanne Field, Bethan Frugtniet, Sheila Palmer-Smith, Jonathan Grant, Judith Pagan, Trudi McDevitt, Terri P McVeigh, Helen Hanson, Nicola Whiffin, Michael Jones, Clare Turnbull","doi":"10.1136/jmg-2024-110034","DOIUrl":"10.1136/jmg-2024-110034","url":null,"abstract":"<p><strong>Background: </strong>The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as 'strong' evidence (PS4) towards pathogenicity.</p><p><strong>Methods: </strong>We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1).</p><p><strong>Results: </strong>PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation.</p><p><strong>Conclusion: </strong>PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"983-991"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125964","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":"Developmental dysplasia of the hip caused by homozygous <i>TRIM33</i> pathogenic variant affecting downstream BMP pathway.","authors":"Maya Gombosh, Regina Proskorovski-Ohayon, Yuval Yogev, Marina Eskin-Schwartz, Noam Hadar, Sarit Aharoni, Vadim Dolgin, Eugen Cohen, Ohad S Birk","doi":"10.1136/jmg-2024-109928","DOIUrl":"10.1136/jmg-2024-109928","url":null,"abstract":"<p><strong>Background: </strong>Developmental dysplasia of the hip (DDH), formerly termed congenital dislocation of the hip, is the most common congenital disease of the musculoskeletal system in newborns. While familial predilection to DDH has been well documented, the molecular genetics/pathways of this common disorder are poorly understood.</p><p><strong>Methods: </strong>Linkage analysis and whole exome sequencing; real-time PCR studies of skin fibroblasts.</p><p><strong>Results: </strong>Consanguineous Bedouin kindred presented with DDH with apparent autosomal recessive heredity. Linkage analysis and whole exome sequencing delineated a single 3.2 Mbp disease-associated chromosome 1 locus (maximal multipoint Logarithm of the Odds score 2.3), containing a single homozygous variant with a relevant expression pattern: addition of threonine in TRIM33 (NM_015906.4); c.1648_1650dup. <i>TRIM33</i> encodes a protein that acts both in the TGF-β and the BMP pathways; however, it has been mostly studied regarding its function in the TGF-β pathway. Since BMPs are known to act in bone formation, we focused on the BMP pathway, in which TRIM33 functions as a transcription factor, both an activator and repressor. Skin fibroblasts of two affected girls and a heterozygous <i>TRIM33</i> variant carrier were assayed through reverse-transcription PCR for expression of genes known to be downstream of TRIM33 in the BMP pathway: fibroblasts of affected individuals showed significantly reduced expression of <i>DLX5</i>, significantly increased expression of <i>BGLAP</i>, increased expression of <i>ALPL</i> and no change in expression of <i>RUNX2</i> or of <i>TRIM33</i> itself.</p><p><strong>Conclusions: </strong>DDH can be caused by a biallelic variant in <i>TRIM33</i>, affecting the BMP pathway.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"959-965"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759251","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}