Eilidh Fummey, Pau Navarro, John-Paul Plazzer, Ian M Frayling, Sara Knott, Albert Tenesa
UNLABELLED: BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genes MLH1 , MSH2 , MSH6 and PMS2 Cancer risk in LS is estimated from cohorts of individuals ascertained by individual or family history of cancer, which may upwardly bias estimates. METHODS: 830 carriers of pathogenic or likely pathogenic ( path_MMR ) MMR gene variants classified by InSiGHT were identified in 454 756 UK Biobank (UKB) participants using whole-exome sequence...
July 14, 2024: Journal of Medical Genetics
Frédéric Loubert, Andrew A House, Catherine Larochelle, Philippe Major, Mark R Keezer
OBJECTIVE: This study aims to develop and internally validate a clinical risk score to predict incident renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) in people with tuberous sclerosis complex (TSC). STUDY DESIGN: Data from 2420 participants in the TSC Alliance Natural History Database were leveraged for these analyses. Logistic regression was used to predict AML and LAM development using 10 early-onset clinical manifestations of TSC as potential predictors, in addition to sex and genetic mutation...
July 8, 2024: Journal of Medical Genetics
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
BACKGROUND: IFIH1 variants have been reported to be associated with immune-related disorders with/without seizures. It is unknown whether IFIH1 variants are associated with common epilepsy without acquired causes and the mechanism underlying phenotypic variation remains elusive. METHODS: 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...
July 4, 2024: Journal of Medical Genetics
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
BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A 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...
July 2, 2024: Journal of Medical Genetics
Naoko Yano, Pin Fee Chong, Kenji K Kojima, Tomoichiro Miyoshi, Ahmad Luqmen-Fatah, Yu Kimura, Kengo Kora, Taisei Kayaki, Kanako Maizuru, Takahiro Hayashi, Atsushi Yokoyama, Masahiko Ajiro, Masatoshi Hagiwara, Teruyuki Kondo, Ryutaro Kira, Junko Takita, Takeshi Yoshida
BACKGROUND: SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a 'copy-and-paste' manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A...
July 2, 2024: Journal of Medical Genetics
Johana Kopčilová, Hana Ptáčková, Tereza Kramářová, Lenka Fajkusová, Kamila Réblová, Jiří Zeman, Tomáš Honzík, Lucie Zdražilová, Josef Zámečník, Patrícia Balážová, Karin Viestová, Miriam Kolníková, Hana Hansíková, Jana Zídková
BACKGROUND: Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in the TRAPPC11 gene. TRAPPC11 structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints...
July 2, 2024: Journal of Medical Genetics
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
BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha ( DNMT3A )-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 DNMT3A , which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML)...
June 27, 2024: Journal of Medical Genetics
Claire Forde, Miriam J Smith, George J Burghel, Naomi Bowers, Nicola Roberts, Tim Lavin, Jane Halliday, Andrew Thomas King, Scott Rutherford, Omar N Pathmanaban, Simon Lloyd, Simon Freeman, Dorothy Halliday, Allyson Parry, Patrick Axon, Juliette Buttimore, Shazia Afridi, Rupert Obholzer, Roger Laitt, Owen Thomas, Stavros Michael Stivaros, Grace Vassallo, D Gareth Evans
OBJECTIVES: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed. METHODS: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service...
June 26, 2024: Journal of Medical Genetics
Qirui Jiang, Junyu Lin, Qianqian Wei, Tianmi Yang, Yanbing Hou, Lingyu Zhang, Ruwei Ou, Yi Xiao, Shichan Wang, Xiaoting Zheng, Chunyu Li, Huifang Shang
BACKGROUND: 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 ( SOD1, TARDBP, FUS, C9orf72 ) and phenotype in ALS. METHODS: 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...
June 17, 2024: Journal of Medical Genetics
Laura Hecher, Esther Gorski-Alberts, Matthias Begemann, Johanna Herwig, Eva Lausberg, Georg Hillebrand, Alexander E Volk, Ingo Kurth, Florian Kraft, Kerstin Kutsche
Homozygous VPS50 variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. VPS50 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 VPS50 variants. She carried a paternally inherited heterozygous nonsense c...
June 14, 2024: Journal of Medical Genetics
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
BACKGROUND: 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...
June 13, 2024: Journal of Medical Genetics
Silvestre Cuinat, Chloé Quélin, Claire Effray, Christèle Dubourg, Gwenaelle Le Bouar, Anne-Sophie Cabaret-Dufour, Philippe Loget, Maia Proisy, Fanny Sauvestre, Mélie Sarreau, Sophie Martin-Berenguer, Claire Beneteau, Sophie Naudion, Vincent Michaud, Benoit Arveiler, Aurélien Trimouille, Pierre Macé, Sabine Sigaudy, Olga Glazunova, Julia Torrents, Laure Raymond, Marie-Hélène Saint-Frison, Tania Attié-Bitach, Mathilde Lefebvre, Yline Capri, Nicolas Bourgon, Christel Thauvin-Robinet, Frédéric Tran Mau-Them, Ange-Line Bruel, Antonio Vitobello, Anne-Sophie Denommé-Pichon, Laurence Faivre, Anne-Claire Brehin, Alice Goldenberg, Sophie Patrier-Sallebert, Alexandre Perani, Benjamin Dauriat, Sylvie Bourthoumieu, Catherine Yardin, Valentine Marquet, Marion Barnique, Maryse Fiorenza-Gasq, Isabelle Marey, Danielle Tournadre, Raïa Doumit, Frédérique Nugues, Tahsin Stefan Barakat, Francisco Bustos, Sylvie Jaillard, Erika Launay, Laurent Pasquier, Sylvie Odent
INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families...
June 7, 2024: Journal of Medical Genetics
Anna Abulí, Eugenia Antolín, Antoni Borrell, Maria Garcia-Hoyos, Fe García Santiago, Irene Gómez Manjón, Nerea Maíz, Cristina González González, Laia Rodríguez-Revenga, Irene Valenzuena Palafoll, Javier Suela
OBJECTIVE: This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care. METHODS: A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals...
June 4, 2024: Journal of Medical Genetics
Xin Yang, Thea M Mooij, Goska Leslie, Lorenzo Ficorella, Nadine Andrieu, Karin Kast, Christian F Singer, Anna Jakubowska, Carla H van Gils, Yen Y Tan, Christoph Engel, Muriel A Adank, Christi J van Asperen, Margreet G E M Ausems, Pascaline Berthet, Margriet J Collee, Jackie A Cook, Jacqueline Eason, Karin Y van Spaendonck-Zwarts, D Gareth Evans, Encarna B Gómez García, Helen Hanson, Louise Izatt, Zoe Kemp, Fiona Lalloo, Christine Lasset, Fabienne Lesueur, Hannah Musgrave, Sophie Nambot, Catherine Noguès, Jan C Oosterwijk, Dominique Stoppa-Lyonnet, Marc Tischkowitz, Vishakha Tripathi, Marijke R Wevers, Emily Zhao, Flora E van Leeuwen, Marjanka K Schmidt, Douglas F Easton, Matti A Rookus, Antonis C Antoniou
BACKGROUND: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres. METHODS: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases)...
June 4, 2024: Journal of Medical Genetics
Steven Smeijers, Hilde Brems, Alexander Verhaeghe, Wim van Paesschen, Johannes van Loon, Seppe Van der Auweraer, Raf Sciot, Dietmar Rudolf Thal, Lieven Lagae, Eric Legius, Tom Theys
Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic congenital condition characterised by ocular, cutaneous and central nervous system involvement. Mosaic activating variants in FGFR1 and KRAS have been reported in several individuals with this syndrome. We report on a patient with neurofibromatosis type 1 (NF1) with a germline pathogenic variant in the NF1 gene and an ECCL phenotype, suggesting ECCL to be part of a spectrum of malformations associated with NF1 pathogenic variants. An anatomical hemispherectomy was performed for intractable epilepsy...
June 1, 2024: Journal of Medical Genetics
Terri Patricia McVeigh, Fiona Lalloo, Kevin J Monahan, Andrew Latchford, Miranda Durkie, Rachael Mein, Emma L Baple, Helen Hanson
No abstract text is available yet for this article.
May 30, 2024: Journal of Medical Genetics
Jing Yang, Ya-Nan Zhang, Ren-Xue Wang, Chen-Zhi Hao, Yiling Qiu, Hao Chi, Wei-Sha Luan, HongYi Tang, Xiu-Juan Zhang, XuXu Sun, Jonathan A Sheps, Victor Ling, Muqing Cao, Jian-She Wang
BACKGROUND AND AIMS: Variants in ZFYVE19 underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism. METHODS: Zfyve19 knockout ( Zfyve19-/- ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients...
May 30, 2024: Journal of Medical Genetics
Elan Hahn, Chloe Mighton, Yael Fisher, Andrew Wong, Vanessa Di Gioacchino, Nicholas Watkins, Justin Mayers, Yvonne Bombard, George S Charames, Jordan Lerner-Ellis
BACKGROUND: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly...
May 28, 2024: Journal of Medical Genetics
Shuo Zhang, Zhenle Pei, Min Xiao, Jing Zhou, Bin Hu, Saijuan Zhu, Xiaoxi Sun, Junping Wu, Caixia Lei, Congjian Xu
BACKGROUND: Balanced insertional translocations (BITs) can increase the risk of infertility, recurrent miscarriages or neonatal birth defects due to chromosomal imbalances in gametes. However, studies on preimplantation genetic testing (PGT) for patients carrying BITs are inadequate. METHODS: A preimplantation genetic genotyping and haplotype analysis approach was developed and implemented in this study. Genome-wide SNP genotyping was performed, followed by core family-based haplotype analysis...
May 26, 2024: Journal of Medical Genetics
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
POT1 is the second most frequently reported gene (after CDKN2A ) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, POT1 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...
May 8, 2024: Journal of Medical Genetics
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