Journal of Medical Genetics最新文献

{"title":"Double gonosomal mosaicism as an unusual hereditary mechanism in familial <i>GRIN2A</i>-related disorder.","authors":"Valentina Cetica, Mara Cavallin, Maria Luisa Ricci, Claudia Mandorlini, Emanuele Bartolini, Elena Parrini, Renzo Guerrini","doi":"10.1136/jmg-2024-110101","DOIUrl":"10.1136/jmg-2024-110101","url":null,"abstract":"<p><p>We aim to describe double gonosomal mosaicism in the <i>GRIN2A</i> gene in a mother who passed on two different pathogenic variants at the same nucleotide to her two affected children. We studied a boy with epilepsy and intellectual disability, along with his sister and mother who exhibited language impairment and learning difficulties without epilepsy. We identified in the proband a splice-site variant in <i>GRIN2A</i> (c.1008-1G>A) inherited from his mother. Subsequent testing of his sister revealed a different change at the same nucleotide c.1008-1G>T, which was also present in the mother's DNA at 3.9% allele frequency. The co-occurrence of two mutational events at the same nucleotide is extremely rare. Since a chance occurrence is unlikely, we hypothesise that a base mismatch may introduce instability triggering a second event. In this family, the mother carries three alleles, of which one is at very low frequency. This complex genetic landscape poses diagnostic challenges since low-level mosaicism may escape detection via conventional methods. Applying specific technology becomes crucial, as double mosaicism might prove to be more prevalent than anticipated severely impacting diagnostic accuracy and genetic counselling.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"999-1002"},"PeriodicalIF":3.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859963","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":"Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients.","authors":"Hortense Thomas, Tom Alix, Émeline Renard, Mathilde Renaud, Justine Wourms, Stéphane Zuily, Bruno Leheup, David Geneviève, Natacha Dreumont, Emmanuelle Schmitt, Myriam Bronner, Marc Muller, Marion Divoux, Marion Wandzel, Jean-Marie Ravel, Mylène Dexheimer, Aurélie Becker, Virginie Roth, Marjolaine Willems, Christine Coubes, Gaëlle Vieville, Françoise Devillard, Élise Schaefer, Sarah Baer, Amélie Piton, Bénédicte Gérard, Marie Vincent, Mathilde Nizon, Benjamin Cogné, Lyse Ruaud, Nathalie Couque, Audrey Putoux, Patrick Edery, Gaëtan Lesca, Nicolas Chatron, Marianne Till, Laurence Faivre, Frédéric Tran-Mau-Them, Jean-Luc Alessandri, Marine Lebrun, Chloé Quélin, Sylvie Odent, Christèle Dubourg, Véronique David, Marie Faoucher, Cyril Mignot, Boris Keren, Élise Pisan, Alexandra Afenjar, Sophie Julia, Éric Bieth, Guillaume Banneau, Alice Goldenberg, Thomas Husson, Dominique Campion, François Lecoquierre, Gaël Nicolas, Camille Charbonnier, Anne De Saint Martin, Sophie Naudion, Manon Degoutin, Sophie Rondeau, Caroline Michot, Valérie Cormier-Daire, Abderrahim Oussalah, Carine Pourié, Laëtitia Lambert, Céline Bonnet","doi":"10.1136/jmg-2024-110031","DOIUrl":"10.1136/jmg-2024-110031","url":null,"abstract":"<p><strong>Background: </strong>Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (<i>DNMT3A</i>)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in <i>DNMT3A</i>, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of <i>DNMT3A</i> are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.</p><p><strong>Methods: </strong>We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.</p><p><strong>Results: </strong>Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in <i>DNMT3A</i>, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.</p><p><strong>Conclusion: </strong>This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"878-885"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468659","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":"Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome.","authors":"Vicken Totten, Gisela Teixido-Tura, Fermina Lopez-Grondona, Paula Fernandez-Alvarez, Amaia Lasa-Aranzasti, Patricia Muñoz-Cabello, Rika Kosaki, Eduardo F Tizzano, Wendy Dewals, Emma Borràs, Elena Gonzalez Cañas, Berta Almoguera, Bart Loeys, Irene Valenzuena","doi":"10.1136/jmg-2024-109861","DOIUrl":"10.1136/jmg-2024-109861","url":null,"abstract":"<p><strong>Background: </strong>Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by <i>DNMT3A</i> heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described.</p><p><strong>Methods: </strong>Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition.</p><p><strong>Results: </strong>We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery.</p><p><strong>Conclusions: </strong>Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"870-877"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498187","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":"Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation.","authors":"Alessandro Geroldi, Alessia Mammi, Andrea Gaudio, Serena Patrone, Andrea La Barbera, Paola Origone, Clarissa Ponti, Francesca Sanguineri, Sara Massucco, Lucio Marinelli, Marina Grandis, Angelo Schenone, Paola Mandich, Emilia Bellone, Fabio Gotta","doi":"10.1136/jmg-2024-110019","DOIUrl":"10.1136/jmg-2024-110019","url":null,"abstract":"<p><strong>Background: </strong>The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.</p><p><strong>Methods: </strong>We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.</p><p><strong>Results: </strong>Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.</p><p><strong>Conclusions: </strong>The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"847-852"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317551","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":"Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.","authors":"Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang","doi":"10.1136/jmg-2024-109909","DOIUrl":"10.1136/jmg-2024-109909","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (<i>SOD1, TARDBP, FUS, C9orf72</i>) and phenotype in ALS.</p><p><strong>Methods: </strong>Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.</p><p><strong>Results: </strong>A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (<i>SOD1</i>, n=65; <i>FUS</i>, n=43; <i>TARDBP</i>, n=27; <i>C9orf72</i>, n=37). <i>SOD1</i> mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). <i>C9orf72</i> expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). <i>SOD1</i> and <i>FUS</i> mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with <i>SOD1</i> mutations, <i>C9orf72</i> expansions and those carrying pathogenic <i>FUS</i> mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with <i>C9orf72</i> expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).</p><p><strong>Conclusion: </strong>Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"839-846"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419441","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":"Complex structural variation and nonsense variant <i>in trans</i> cause <i>VPS50</i>-related disorder.","authors":"Laura Hecher, Esther Gorski-Alberts, Matthias Begemann, Johanna Herwig, Eva Lausberg, Georg Hillebrand, Alexander E Volk, Ingo Kurth, Florian Kraft, Kerstin Kutsche","doi":"10.1136/jmg-2024-109983","DOIUrl":"10.1136/jmg-2024-109983","url":null,"abstract":"<p><p>Homozygous <i>VPS50</i> variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. <i>VPS50</i> encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic <i>VPS50</i> variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire <i>VPS50</i> gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both <i>VPS50</i> variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with <i>VPS50</i> pathogenic variants. The <i>VPS50</i>-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"833-838"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321028","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>IFIH1</i> variants are associated with generalised epilepsy preceded by febrile seizures.","authors":"Wang Song, Wen-Jun Bian, Hua Li, Qing-Hui Guo, Jie Wang, Bin Tang, Jia-Yuan Zhang, Wei Wei, Xiao-Rong Liu, Wei-Ping Liao, Bin Li, Na He","doi":"10.1136/jmg-2024-109950","DOIUrl":"10.1136/jmg-2024-109950","url":null,"abstract":"<p><strong>Background: </strong><i>IFIH1</i> variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether <i>IFIH1</i> variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive.</p><p><strong>Methods: </strong>Trio-based whole-exome sequencing was performed on patients with febrile seizures or epilepsy with antecedent febrile seizures. Previously reported variants were systematically reviewed to investigate genotype-phenotype associations.</p><p><strong>Results: </strong>Two de novo heterozygous and three biallelic missense variants were identified in five patients with generalised epilepsy with antecedent febrile seizures. The variants were predicted to be damaging by in silico tools and were associated with hydrogen bonding changes to neighbouring amino acids or decreased protein stability. Patients exhibited an early onset age and became seizure-free with favourable outcome. Further analysis revealed that de novo missense variants located in the Hel region resulted in seizures with multiple neurological abnormalities, while those in the pincer domain or C-terminal domain led to seizures with normal neurodevelopment, suggesting a sub-molecular effect. Biallelic missense variants, which were inherited from unaffected parents and presented low allele frequencies in general populations, were associated with seizures without neurological abnormalities. Truncation variants were related to refractory epilepsy and severe developmental delay, suggesting a genotype-phenotype correlation. <i>IFIH1</i> is predominantly expressed in the neonatal stage and decreases dramatically in the adulthood, which is consistent with the early onset age and favourable outcome of the patients.</p><p><strong>Conclusions: </strong><i>IFIH1</i> variants are potentially associated with generalised epilepsy with antecedent febrile seizures. The sub-molecular implication and genotype-phenotype association help explain phenotype variations of <i>IFIH1</i> variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"895-903"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534597","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":"Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank.","authors":"Eilidh Fummey, Pau Navarro, John-Paul Plazzer, Ian M Frayling, Sara Knott, Albert Tenesa","doi":"10.1136/jmg-2023-109791","DOIUrl":"10.1136/jmg-2023-109791","url":null,"abstract":"<p><p>BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i> and <i>PMS2</i> Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates.</p><p><strong>Methods: </strong>830 carriers of pathogenic or likely pathogenic (<i>path_MMR</i>) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial and breast cancer (BC).</p><p><strong>Results: </strong>Cumulative incidence of colorectal and endometrial cancer (EC) by age 70 years was elevated in <i>path_MMR</i> carriers compared with non-carriers (colorectal: 11.8% (95% confidence interval (CI): 9.5% to 14.6%) vs 1.7% (95% CI: 1.6% to 1.7%), endometrial: 13.4% (95% CI: 10.2% to 17.6%) vs 1.0% (95% CI: 0.9% to 1.0%)), but the magnitude of this increase differed between genes. Cumulative BC incidence by age 70 years was not elevated in <i>path_MMR</i> carriers compared with non-carriers (8.9% (95% CI: 6.3% to 12.4%) vs 7.5% (95% CI: 7.4% to 7.6%)). Cumulative cancer incidence estimates in UKB were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated EC risk in carriers of pathogenic <i>PMS2</i> variants in UKB.</p><p><strong>Conclusion: </strong>These results support offering incidentally identified carriers of any <i>path_MMR</i> surveillance to manage colorectal cancer risk. Incidentally identified carriers of pathogenic variants in <i>MLH1</i>, <i>MSH2</i> and <i>MSH6</i> would also benefit from interventions to reduce EC risk. The results suggest that BC is not an LS-related cancer.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"861-869"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616678","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":"<i>POT1</i> and multiple primary melanomas: the dermatological phenotype.","authors":"Ellie J Maas, Emily DeBortoli, Vaishnavi Nathan, Ned P Freeman, Adam Mothershaw, Darren J Smit, Brigid Betz-Stablein, Lauren G Aoude, Mitchell S Stark, Richard A Sturm, H Peter Soyer, Aideen M McInerney-Leo","doi":"10.1136/jmg-2023-109637","DOIUrl":"10.1136/jmg-2023-109637","url":null,"abstract":"<p><p><i>POT1</i> is the second most frequently reported gene (after <i>CDKN2A</i>) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, <i>POT1</i> phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72^×10-12) in carriers compared with a control population. Majority of naevi were on the probands' back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant <i>POT1</i> variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"891-894"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898138","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>JMG</i> at 60.","authors":"Huw Dorkins","doi":"10.1136/jmg-2024-110287","DOIUrl":"10.1136/jmg-2024-110287","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"823"},"PeriodicalIF":3.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055810","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}