Journal of Medical Genetics最新文献

{"title":"<i>TFAP2E</i> is implicated in central nervous system, orofacial and maxillofacial anomalies.","authors":"Jeshurun C Kalanithy, Enrico Mingardo, Jil D Stegmann, Ramgopal Dhakar, Tikam Chand Dakal, Jill A Rosenfeld, Wen-Hann Tan, Stephanie A Coury, Audrey C Woerner, Jessica Sebastian, Paul A Levy, Leah R Fleming, Lea Waffenschmidt, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Bimaljeet K Babra, Andrea Christ, Britta Eiberger, Selina Hölzel, Clara Vidic, Felix Häberlein, Nina Ishorst, Juan E Rodriguez-Gatica, Behnaz Pezeshkpoor, Patrick A Kupczyk, Olivier M Vanakker, Sara Loddo, Antonio Novelli, Maria L Dentici, Albert Becker, Holger Thiele, Jennifer E Posey, James R Lupski, Alina C Hilger, Heiko M Reutter, Waltraut M Merz, Gabriel C Dworschak, Benjamin Odermatt","doi":"10.1136/jmg-2023-109799","DOIUrl":"10.1136/jmg-2023-109799","url":null,"abstract":"<p><strong>Background: </strong>Previous studies in mouse, <i>Xenopus</i> and zebrafish embryos show strong <i>tfap2e</i> expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (<i>TFAP2E)</i> in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown.</p><p><strong>Methods: </strong>Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation prompted <i>TFAP2E</i> gene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression of <i>tfap2e</i> in fluorescent zebrafish reporter lines using in vivo microscopy. Computational structural protein modelling of the identified human variants was performed.</p><p><strong>Results: </strong>In total, exome survey identified novel or ultra-rare heterozygous missense variants in <i>TFAP2E</i> in seven individuals from five independent families with predominantly CNS, orofacial and maxillofacial anomalies. One variant was found de novo and another variant segregated in an affected multiplex family. Protein modelling of the identified variants indicated potential distortion of TFAP2E in the transactivation or dimerisation domain. MO KD and CRISPR/Cas9 knockout of <i>tfap2e</i> in zebrafish revealed hydrocephalus and a significant reduction of brain volume, consistent with a microencephaly phenotype. Furthermore, mRNA overexpression of <i>TFAP2E</i> indicates dosage-sensitive phenotype expression. In addition, zebrafish showed orofacial and maxillofacial anomalies following <i>tfap2e</i> KD, recapitulating the human phenotype.</p><p><strong>Conclusion: </strong>Our human genetic data and analysis of Tfap2e manipulation in zebrafish indicate a potential role of <i>TFAP2E</i> in human CNS, orofacial and maxillofacial anomalies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"126-137"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11777392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881570","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":"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":"57-61"},"PeriodicalIF":3.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916899/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing variant of uncertain significance (VUS) interpretation in neurogenetics: collaborative experiences from a tertiary care centre.","authors":"Kayla Horowitz, Nellie H Fotopoulos, Alana J Mistry, Justin Simo, Miranda Medeiros, Isabela D Bucco, Mia Ginsberg, Emily Dwosh, Roberta La Piana, Guy A Rouleau, Allison A Dilliott, Sali M K Farhan","doi":"10.1136/jmg-2024-110122","DOIUrl":"10.1136/jmg-2024-110122","url":null,"abstract":"<p><strong>Background: </strong>The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population.</p><p><strong>Methods: </strong>VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions and discuss nuances of VUS result communication.</p><p><strong>Results: </strong>In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritisation of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. We thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions.</p><p><strong>Conclusions: </strong>The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices ensures equitable knowledge dissemination among HCPs and effective incorporation of uncertain genetic results into patient care.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"37-45"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639215","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":"Novel <i>HYLS1</i> variants associated with Joubert syndrome suggest potential genotype-phenotype correlates.","authors":"Simone Gana, Fulvio D'Abrusco, Roberta Nicotra, Chiara Ghiberti, Guido Catalano, Elisa Rognone, Anna Pichiecchio, Sabrina Signorini, Enza Maria Valente","doi":"10.1136/jmg-2024-110308","DOIUrl":"10.1136/jmg-2024-110308","url":null,"abstract":"<p><p>Joubert syndrome (JS) is an inherited neurodevelopmental ciliopathy with wide clinical and genetic heterogeneity, whose paradigmatic sign is a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign'. Recessive pathogenic variants in the <i>HYLS1</i> gene are associated with hydrolethalus syndrome (HLS), a severe disorder characterised by multiple developmental defects leading to intrauterine or perinatal death. However, <i>HYLS1</i> biallelic variants were also reported in three individuals with JS.Here, we report a fourth patient with a purely neurological JS carrying two compound heterozygous missense variants in the <i>HYLS1</i> gene. Notably, while all patients with lethal HLS had both variants falling within the highly conserved HYLS-1 Box, the four patients with milder JS phenotype featured at least one variant external to this evolutionary conserved domain, suggesting a possible correlation between the mutation site and the severity of the phenotype.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"3-5"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769786","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":"Six at Sixty. Commentary on identification of the <i>PTEN</i> gene as a major contributor to autism spectrum disorder.","authors":"Merlin G Butler","doi":"10.1136/jmg-2024-110470","DOIUrl":"10.1136/jmg-2024-110470","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"48-52"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791744","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":"Long-read sequencing for detection and subtyping of Prader-Willi and Angelman syndromes.","authors":"Vahid Akbari, Sarah Dada, Yaoqing Shen, Katherine Dixon, Duha Hejla, Andrew Galbraith, Sanaa Choufani, Rosanna Weksberg, Cornelius F Boerkoel, Laura Stewart, William T Gibson, Steven J M Jones","doi":"10.1136/jmg-2024-110115","DOIUrl":"10.1136/jmg-2024-110115","url":null,"abstract":"<p><p>Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband's PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada <i>et al</i>; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and <i>UBE3A</i> indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"32-36"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622214","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":"Charis Eng: an appreciation.","authors":"William D Foulkes, Shirley V Hodgson, Eamonn R Maher, Joanne Ngeow, Willie Reardon, Richard Trembath","doi":"10.1136/jmg-2024-110513","DOIUrl":"https://doi.org/10.1136/jmg-2024-110513","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 1","pages":"46-47"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909792","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":"Clinical and mutational signatures of <i>CRB1</i>-associated retinopathies: a multicentre study.","authors":"Mo-Ying Wang, Feng-Juan Gao, Yu-Qiao Ju, Lin-Ying Guo, Cong Duan, Qing Chang, Ting Zhang, Ge-Zhi Xu, Hui Du, Yuan Zong, Xin Huang","doi":"10.1136/jmg-2024-110289","DOIUrl":"10.1136/jmg-2024-110289","url":null,"abstract":"<p><strong>Background: </strong>To delineate the clinical and mutational signatures of patients with <i>CRB1</i>-associated retinopathies.</p><p><strong>Methods: </strong>This multicentre retrospective cohort study involved 40 patients with <i>CRB1</i> mutations and 40 age-matched and gender-matched inherited retinal diseases (IRDs). The detailed phenotyping and genotyping characteristics and genotype‒phenotype correlations of the patients were analysed.</p><p><strong>Results: </strong>The mean age of <i>CRB1</i> cohort was 27.33±14.63 years. Results showed that yellowish geographic macular degeneration (66.67%), small white or yellow dots (65.6%), hyperopia (62.5%), abnormally laminated retina (61.61%), epiretinal membrane (60.6%) and nummular pigment deposits (50%) were the most common signatures in patients with <i>CRB1</i> mutations. These clinical signatures were notably more prevalent among <i>CRB1</i> patients than among individuals in other IRD groups (p<0.001). Early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) patients are more likely to present these signatures than retinitis pigmentosa (RP) and macular dystrophy (MD) patients. Furthermore, a significant reduction in central foveal thickness coupled with pronounced thickening of the peripheral retina was observed more distinctly in patients with EOSRD/LCA (p<0.001). The choroidal thickness was not significantly altered compared to the normal controls, but was markedly reduced in the other IRD groups (p<0.001). 55 pathogenic variants were identified, 20 of which were novel. Null mutations were associated with EOSRD/LCA patients, and missense mutations were more prevalent in MD and RP patients.</p><p><strong>Conclusions: </strong>Key clinical and mutational signatures were demonstrated in this study, providing a comprehensive update on <i>CRB1</i>-associated retinopathies that will aid in diagnosis and lay the foundation for future therapeutic studies.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"6-14"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576422","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> in 2025.","authors":"Huw Dorkins","doi":"10.1136/jmg-2024-110548","DOIUrl":"https://doi.org/10.1136/jmg-2024-110548","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 1","pages":"1"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909791","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":"Authors' response to the commentary by Kivela <i>et al</i> on Hany <i>et al</i> (2024).","authors":"Alan J Mighell, Chris Inglehearn","doi":"10.1136/jmg-2024-110345","DOIUrl":"10.1136/jmg-2024-110345","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"2"},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391094","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}