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Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement J. Med. Genet. (IF 4.0) Pub Date : 2024-03-12 Didier Lacombe, Agnès Bloch-Zupan, Cecilie Bredrup, Edward B Cooper, Sofia Douzgou Houge, Sixto García-Miñaúr, Hülya Kayserili, Lidia Larizza, Vanesa Lopez Gonzalez, Leonie A Menke, Donatella Milani, Francesco Saettini, Cathy A Stevens, Lloyd Tooke, Jill A Van der Zee, Maria M Van Genderen, Julien Van-Gils, Jane Waite, Jean-Louis Adrien, Oliver Bartsch, Pierre Bitoun, Antonia H M Bouts, Anna M Cueto-González
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes ( CREBBP , EP300 ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and
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Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability J. Med. Genet. (IF 4.0) Pub Date : 2024-03-08 Claire E L Smith, Virginie Laugel-Haushalter, Ummey Hany, Sunayna Best, Rachel L Taylor, James A Poulter, Saskia B Wortmann, Rene G Feichtinger, Johannes A Mayr, Suhaila Al Bahlani, Georgios Nikolopoulos, Alice Rigby, Graeme C Black, Christopher M Watson, Sahar Mansour, Chris F Inglehearn, Alan J Mighell, Agnès Bloch-Zupan
Background Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been
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Survey of service needs to embed genome sequencing for motor neuron disease in neurology in the English National Health Service J. Med. Genet. (IF 4.0) Pub Date : 2024-03-08 Jade Howard, Hilary L Bekker, Christopher J McDermott, Alisdair McNeill
All people with motor neuron disease (pwMND) in England are eligible for genome sequencing (GS), with panel-based testing. With the advent of genetically targeted MND treatments, and increasing demand for GS, it is important that clinicians have the knowledge and skills to support pwMND in making informed decisions around GS. We undertook an online survey of clinical genomic knowledge and genetic counselling
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Cerebral visual impairment: genetic diagnoses and phenotypic associations J. Med. Genet. (IF 4.0) Pub Date : 2024-03-08 Emogene Shaw, Ian Flitcroft, Richard Bowman, Kate Baker
Background Cerebral visual impairment (CVI) is the most common form of paediatric visual impairment in developed countries. CVI can arise from a host of genetic or acquired causes, but there has been limited research to date on CVI in the context of genetic disorders. Methods We carried out a retrospective analysis of genotypic and phenotypic data for participants with CVI within the DECIPHER database
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Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights J. Med. Genet. (IF 4.0) Pub Date : 2024-03-08 Burcu Atasu, Javier Simón-Sánchez, Hasmet Hanagasi, Basar Bilgic, Ann-Kathrin Hauser, Gamze Guven, Peter Heutink, Thomas Gasser, Ebba Lohmann
Background Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia
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Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome J. Med. Genet. (IF 4.0) Pub Date : 2024-03-08 Pauline Arnaud, Zakaria Mougin, Genevieve Baujat, Valérie Drouin-Garraud, Salima El Chehadeh, Laurent Gouya, Sylvie Odent, Guillaume Jondeau, Catherine Boileau, Nadine Hanna, Carine Le Goff
Background Marfan syndrome (MFS) is a multisystem disease with a unique combination of skeletal, cardiovascular and ocular features. Geleophysic/acromicric dysplasias (GPHYSD/ACMICD), characterised by short stature and extremities, are described as ‘the mirror image’ of MFS. The numerous FBN1 pathogenic variants identified in MFS are located all along the gene and lead to the same final pathogenic
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Comparing the frequency of variants of uncertain significance (VUS) between ancestry groups in a paediatric epilepsy cohort J. Med. Genet. (IF 4.0) Pub Date : 2024-03-07 Bree E Martin, Tristan Sands, Louise Bier, Amanda Bergner, Amelia K Boehme, Natalie Lippa
Background Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation
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NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways J. Med. Genet. (IF 4.0) Pub Date : 2024-03-05 Sipeng Zhang, Jie Yang, Dandan Ji, Xinyi Meng, Chonggui Zhu, Gang Zheng, Joseph Glessner, Hui-Qi Qu, Yuechen Cui, Yichuan Liu, Wei Wang, Xiumei Li, Hao Zhang, Zhanjie Xiu, Yan Sun, Ling Sun, Jie Li, Hakon Hakonarson, Jin Li, Qianghua Xia
Background Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. Methods Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant
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Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation J. Med. Genet. (IF 4.0) Pub Date : 2024-02-27 Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Li Bai, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, Zhaoxia Wang
Background Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report
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Skewed X-chromosome inactivation drives the proportion of DNAAF6-defective airway motile cilia and variable expressivity in primary ciliary dyskinesia J. Med. Genet. (IF 4.0) Pub Date : 2024-02-26 Lucie Thomas, Laurence Cuisset, Jean-Francois Papon, Aline Tamalet, Isabelle Pin, Rola Abou Taam, Catherine Faucon, Guy Montantin, Sylvie Tissier, Philippe Duquesnoy, Florence Dastot - Le Moal, Bruno Copin, Nathalie Carion, Bruno Louis, Sandra Chantot-Bastaraud, Jean-Pierre Siffroi, Rana Mitri, André Coste, Estelle Escudier, Guillaume Thouvenin, Serge Amselem, Marie Legendre
Background Primary ciliary dyskinesia (PCD) is a rare airway disorder caused by defective motile cilia. Only male patients have been reported with pathogenic mutations in X-linked DNAAF6 , which result in the absence of ciliary dynein arms, whereas their heterozygous mothers are supposedly healthy. Our objective was to assess the possible clinical and ciliary consequences of X-chromosome inactivation
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De novo heterozygous missense variants in CELSR1 as cause of fetal pleural effusions and progressive fetal hydrops J. Med. Genet. (IF 4.0) Pub Date : 2024-02-22 Maayke A de Koning, Paula A Pimienta Ramirez, Monique C Haak, Xiao Han, Martina HA Ruiterkamp-Versteeg, Nicole de Leeuw, Ulrich A Schatz, Moneef Shoukier, Esther Rieger-Fackeldey, Javier U Ortiz, Sjoerd G van Duinen, Willemijn M Klein, Ruben S G M Witlox, Richard H Finnell, Gijs W E Santen, Yunping Lei, Manon Suerink
Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr)
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Variant reclassification and clinical implications J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Nicola Walsh, Aislinn Cooper, Adrian Dockery, James J O'Byrne
Genomic technologies have transformed clinical genetic testing, underlining the importance of accurate molecular genetic diagnoses. Variant classification, ranging from benign to pathogenic, is fundamental to these tests. However, variant reclassification, the process of reassigning the pathogenicity of variants over time, poses challenges to diagnostic legitimacy. This review explores the medical
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Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Marie Morimoto, Elena-Raluca Nicoli, Chulaluck Kuptanon, Joseph C Roney, Jenny Serra-Vinardell, Prashant Sharma, David R Adams, John I Gallin, Steven M Holland, Sergio D Rosenzweig, Jose Barbot, Carla Ciccone, Marjan Huizing, Camilo Toro, William A Gahl, Wendy J Introne, May Christine V Malicdan
Introduction Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, a bleeding diathesis, immunological dysfunction and neurological impairment. Bi-allelic loss-of-function variants in LYST cause CHS. LYST encodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function. Methods To further
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Whole exome sequencing of 491 individuals with inherited retinal diseases reveals a large spectrum of variants and identification of novel candidate genes J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Tamar Hayman, Talya Millo, Karen Hendler, Itay Chowers, Menachem Gross, Eyal Banin, Dror Sharon
Background Inherited retinal diseases (IRDs) include a range of vision loss conditions caused by variants in different genes. The clinical and genetic heterogeneity make identification of the genetic cause challenging. Here, a cohort of 491 unsolved cases from our cohort of Israeli and Palestinian families with IRDs underwent whole exome sequencing (WES), including detection of CNVs as well as single
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Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Anthony M Vandersteen, Ruwan A Weerakkody, David A Parry, Christina Kanonidou, Daniel J Toddie-Moore, Jana Vandrovcova, Rebecca Darlay, Javier Santoyo-Lopez, Alison Meynert, NIHR BioResource, Hanadi Kazkaz, Rodney Grahame, Carole Cummings, Marion Bartlett, Neeti Ghali, Angela F Brady, F Michael Pope, Fleur S van Dijk, Heather J Cordell, Timothy J Aitman
Background The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown. Methods Whole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients
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Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1 J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Ichiro Takeuchi, Kanako Tanase-Nakao, Ayame Ogawa, Tohru Sugawara, Osuke Migita, Makoto Kashima, Touko Yamazaki, Akihiro Iguchi, Yasuhiro Naiki, Toru Uchiyama, Junya Tamaoki, Hiroki Maeda, Hirotaka Shimizu, Toshinao Kawai, Kosuke Taniguchi, Hiromi Hirata, Makoto Kobayashi, Kimikazu Matsumoto, Kiyoshi Naruse, Kenichiro Hata, Hidenori Akutsu, Takashi Kato, Satoshi Narumi, Katsuhiro Arai, Akira Ishiguro
DNA polymerase epsilon (Pol ε), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ε have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE , encoding Pol ε catalytic subunit A (POLE1), in siblings with a syndromic form
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Loss-of-function variants in ZEB1 cause dominant anomalies of the corpus callosum with favourable cognitive prognosis J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Solveig Heide, Emanuela Argilli, Stéphanie Valence, Lucile Boutaud, Nathalie Roux, Cyril Mignot, Caroline Nava, Boris Keren, Kim Giraudat, Anne Faudet, Anna Gerasimenko, Catherine Garel, Eleonore Blondiaux, Agnès Rastetter, David Grevent, Carolyn Le, Lisa Mackenzie, Linda Richards, Tania Attié-Bitach, Christel Depienne, Elliott Sherr, Delphine Héron
Background The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered. Methods Through a collaborative work, we describe here
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Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Hildegard Nikki Hall, David Parry, Mihail Halachev, Kathleen A Williamson, Kevin Donnelly, Jose Campos Parada, Shipra Bhatia, Jeffrey Joseph, Simon Holden, Trine E Prescott, Pierre Bitoun, Edwin P Kirk, Ruth Newbury-Ecob, Katherine Lachlan, Juan Bernar, Veronica van Heyningen, David R FitzPatrick, Alison Meynert
Background Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting the PAX6 locus. Methods Short-read whole genome sequencing was performed on 51 (39 affected)
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CCDC66 mutations are associated with high myopia through affected cell mitosis J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Xiaozhen Chen, Ping Tong, Ying Jiang, Zhe Cheng, Liyu Zang, Zhikuan Yang, Weizhong Lan, Kun Xia, Zhengmao Hu, Qi Tian
Background High myopia (HM) refers to an eye refractive error exceeding −5.00 D, significantly elevating blindness risk. The underlying mechanism of HM remains elusive. Given the extensive genetic heterogeneity and vast genetic base opacity, it is imperative to identify more causative genes and explore their pathogenic roles in HM. Methods We employed exome sequencing to pinpoint the causal gene in
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Risk perception and surveillance uptake in individuals at increased risk for pancreatic ductal adenocarcinoma J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Denis Nguyen, Ophir Gilad, Christine M Drogan, Zoe Eilers, Chuanhong Liao, Sonia S Kupfer
Background Surveillance for pancreatic ductal adenocarcinoma (PDAC) is recommended for high-risk individuals with genetic variants in PDAC-associated genes and/or family history. Surveillance uptake and adherence may depend on the perception of PDAC risk and cancer worry. We aimed to determine PDAC risk perception in at-risk individuals and assess factors associated with PDAC surveillance uptake. Methods
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Functional annotation with expression validation identifies novel metastasis-relevant genes from post-GWAS risk loci in sporadic colorectal carcinomas J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Lai Fun Thean, Michelle Wong, Michelle Lo, Iain Tan, Evelyn Wong, Fei Gao, Emile Tan, Choong Leong Tang, Peh Yean Cheah
Background Colorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients. Methods A case-case genome-wide
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Mosaic BRCA1 promoter methylation contribution in hereditary breast/ovarian cancer pedigrees J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Mathias Schwartz, Sabrina Ibadioune, Albain Chansavang, Sophie Vacher, Sandrine M Caputo, Hélène Delhomelle, Jennifer Wong, Khadija Abidallah, Virginie Moncoutier, Véronique Becette, Tatiana Popova, Voreak Suybeng, Antoine De Pauw, Marc-Henri Stern, Chrystelle Colas, Emmanuelle Mouret-Fourme, Dominique Stoppa-Lyonnet, Lisa Golmard, Ivan Bieche, Julien Masliah-Planchon
Purpose Mosaic BRCA1 promoter methylation ( BRCA1 meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1 meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. Patients Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no
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Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Rivka Birnbaum, Shlomit Ezer, Nava Shaul Lotan, Avital Eilat, Keren Sternlicht, Lilach Benyamini, Orit Reish, Tzipora Falik-Zaccai, Gali Ben-Gad, Raya Rod, Reeval Segel, Katherine Kim, Barabra Burton, Catherine E Keegan, Mallory Wagner, Lindsay B Henderson, Nofar Mor, Ortal Barel, Yoel Hirsch, Vardiella Meiner, Orly Elpeleg, Tamar Harel, Hagar Mor-Shakad
Background Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented
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Reduced penetrance of gene variants causing amyotrophic lateral sclerosis J. Med. Genet. (IF 4.0) Pub Date : 2024-03-01 Andrew G L Douglas, Diana Baralle
Background Amyotrophic lateral sclerosis overlaps aetiologically and genetically with frontotemporal dementia and occurs in both familial and apparently sporadic forms. The most commonly implicated genes are C9orf72 , SOD1 , TARDBP and FUS . Penetrance of disease-causing variants in these genes is known to be incomplete, but has not been well studied at population level. Objective We sought to determine
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Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder J. Med. Genet. (IF 4.0) Pub Date : 2024-02-13 Bruna Pereira Marquezini, Mariana Moysés-Oliveira, Anna Kloster, Lais Cunha, Tais Bassani Deconto, Amanda Cristina Mosini, Pedro Guerreiro, Mayara Paschalidis, Luana Nayara Gallego Adami, Monica Levy Andersen, Sergio Tufik
Pogo transposable element-derived protein with ZNF domain ( POGZ ) gene encodes a chromatin regulator and rare variants on this gene have been associated with a broad spectrum of neurodevelopmental disorders, such as White-Sutton syndrome. Patient clinical manifestations frequently include developmental delay, autism spectrum disorder and obesity. Sleep disturbances are also commonly observed in these
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Bi-allelic variants in chromatoid body protein TDRD6 cause spermiogenesis defects and severe oligoasthenoteratozoospermia in humans J. Med. Genet. (IF 4.0) Pub Date : 2024-02-10 Rui Guo, Huan Wu, Xiaoyu Zhu, Guanxiong Wang, Kaiqin Hu, Kuokuo Li, Hao Geng, Chuan Xu, Chenwan Zu, Yang Gao, Dongdong Tang, Yunxia Cao, Xiaojin He
Background The association between the TDRD6 variants and human infertility remains unclear, as only one homozygous missense variant of TDRD6 was found to be associated with oligoasthenoteratozoospermia (OAT). Methods Whole-exome sequencing and Sanger sequencing were employed to identify potential pathogenic variants of TDRD6 in infertile men. Histology, immunofluorescence, immunoblotting and ultrastructural
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Improved sensitivity for detection of pathogenic variants in familial NF2-related schwannomatosis J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Cristina Perez-Becerril, George J Burghel, Claire Hartley, Charles F Rowlands, D Gareth Evans, Miriam J Smith
Purpose To determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial NF2 -related schwannomatosis. Methods We conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria for NF2 -related schwannomatosis. In addition to the current clinical screening techniques, targeted next-generation
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Heterozygous deletion of HOXC10-HOXC9 causes lower limb abnormalities in congenital vertical talus J. Med. Genet. (IF 4.0) Pub Date : 2024-01-31 Liheng Chen, Shuoyang Zhao, Wenxia Song, Lihong Wang, Zerong Yao, Jianfei Gao, Xiaoze Li
Genes involved in limb patterning are sensitive to the gene dosage effect.1 In this brief communication, we examine the possible associations between the heterozygous deletion of HOXC10-HOXC9 and congenital vertical talus (CVT). In 2016, Alvarado et al 2 reported the associations between deletions of 5′ HOXC genes ( HOXC12, HOXC13 ) and CVT; however, subsequent reports on CVT-related genes have been
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BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome J. Med. Genet. (IF 4.0) Pub Date : 2024-01-31 Kerry A Miller, David A Cruz Walma, Daniel M Pinkas, Rebecca S Tooze, Joshua C Bufton, William Richardson, Charlotte E Manning, Alice E Hunt, Julien Cros, Verity Hartill, Michael J Parker, Simon J McGowan, Stephen R F Twigg, Rod Chalk, David Staunton, David Johnson, Andrew O M Wilkie, Alex N Bullock
Introduction KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome. Methods Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising
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ZNF142 mutation causes sex-dependent neurologic disorder J. Med. Genet. (IF 4.0) Pub Date : 2024-01-31 Regina Proskorovski-Ohayon, Marina Eskin-Schwartz, Zamir Shorer, Rotem Kadir, Daniel Halperin, Max Drabkin, Yuval Yogev, Sarit Aharoni, Noam Hadar, Hagit Cohen, Ekaterina Eremenko, Yonatan Perez, Ohad S Birk
Background Sex-specific predilection in neurological diseases caused by mutations in autosomal genes is a phenomenon whose molecular basis is poorly understood. We studied females of consanguineous Bedouin kindred presenting with severe global developmental delay and epilepsy. Methods Linkage analysis, whole exome sequencing, generation of CRISPR/cas9 knock-in mice, mouse behaviour and molecular studies
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Childhood-onset hypertrophic cardiomyopathy caused by thin-filament sarcomeric variants J. Med. Genet. (IF 4.0) Pub Date : 2024-01-31 Gabrielle Norrish, Marisa Gasparini, Ella Field, Elena Cervi, Juan Pablo Kaski
Up to 20% of children with sarcomeric hypertrophic cardiomyopathy (HCM) have disease-causing variants in genes coding for thin-filament proteins. However, data on genotype-phenotype correlations for thin-filament disease are limited. This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease. Longitudinal
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Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort J. Med. Genet. (IF 4.0) Pub Date : 2024-01-31 Xiaohong Yan, Jing Wang, Wen Yang, Linke Li, Tian Shen, Jia Geng, Qian Zhang, Mingjun Zhong, Wenyu Xiong, Fengxiao Bu, Yu Lu, Yu Zhao, Jing Cheng, Huijun Yuan
Background Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics. Methods We screened SALL1 and DACT1 variants using
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Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals J. Med. Genet. (IF 4.0) Pub Date : 2024-01-30 Lottie D. Morison, Milou G.P. Kennis, Dmitrijs Rots, Arianne Bouman, Joost Kummeling, Elizabeth Palmer, Adam P. Vogel, Frederique Liegeois, Amanda Brignell, Siddharth Srivastava, Zoe Frazier, Di Milnes, Himanshu Goel, David J. Amor, Ingrid E. Scheffer, Tjitske Kleefstra, Angela T. Morgan
Objectives Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. Method 103 individuals with Kleefstra syndrome (40 males, median
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Mosaic RASopathies concept: different skin lesions, same systemic manifestations? J. Med. Genet. (IF 4.0) Pub Date : 2024-01-30 Marie-Anne Morren, Heidi Fodstad, Hilde Brems, Nicola Bedoni, Emmanuella Guenova, Martine Jacot-Guillarmod, Kanetee Busiah, Fabienne Giuliano, Michel Gilliet, Isis Atallah
Background Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in HRAS , KRAS , and less frequently , NRAS and BRAF may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders
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Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis J. Med. Genet. (IF 4.0) Pub Date : 2024-01-30 Ilse Luyckx, Isaac Scott Walton, Nele Boeckx, Kristof Van Schil, Chingyiu Pang, Mania De Praeter, Helen Lord, Christopher Mark Watson, David T Bonthron, Lut Van Laer, Andrew O M Wilkie, Bart Loeys
Background SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a
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Genotype and phenotype correlation of PHACTR1-related neurological disorders J. Med. Genet. (IF 4.0) Pub Date : 2024-01-25 Zhao Xu, Lynette Sadleir, Himanshu Goel, Xianru Jiao, Yue Niu, Zongpu Zhou, Guillem de Valles-Ibáñez, Gemma Poke, Michael Hildebrand, Nico Lieffering, Jiong Qin, Zhixian Yang
Background PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein–protein interaction. Methods We identified seven patients with PHACTR1 variants by trio-based whole-exome
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Further characterisation of ARX-related disorders in females due to inherited or de novo variants J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Mathilde Gras, Solveig Heide, Boris Keren, Stéphanie Valence, Catherine Garel, Sandra Whalen, Anna C Jansen, Kathelijn Keymolen, Katrien Stouffs, Mélanie Jennesson, Céline Poirsier, Gaetan Lesca, Christel Depienne, Caroline Nava, Agnès Rastetter, Aurore Curie, Laurence Cuisset, Vincent Des Portes, Mathieu Milh, Perrine Charles, Cyril Mignot, Delphine Héron
The Aristaless-related homeobox ( ARX ) gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of ARX -related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete
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Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Pauline Marzin, Sophie Rondeau, Jean-Luc Alessandri, Klaus Dieterich, Carine le Goff, Clémentine Mahaut, Sandra Mercier, Caroline Michot, Oana Moldovan, Gianmaria Miolo, Massimiliano Rossi, Julien Van-Gils, Christine Francannet, Matthieu P Robert, Jean-Philippe Jaïs, Céline Huber, Valerie Cormier-Daire
Background Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations. WMS is characterised by specific ophthalmological abnormalities, although cardiovascular defects have also been reported. Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10 , ADAMTS17 and
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SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Max Drabkin, Matan M Jean, Yael Noy, Daniel Halperin, Yuval Yogev, Ohad Wormser, Regina Proskorovski-Ohayon, Vadim Dolgin, Noam Levaot, Vlad Brumfeld, Shira Ovadia, Mor Kishner, Udi Kazenell, Karen B Avraham, Ilan Shelef, Ohad S Birk
Background Otosclerosis is a common cause of adult-onset progressive hearing loss, affecting 0.3%–0.4% of the population. It results from dysregulation of bone homeostasis in the otic capsule, most commonly leading to fixation of the stapes bone, impairing sound conduction through the middle ear. Otosclerosis has a well-known genetic predisposition including familial cases with apparent autosomal dominant
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Mutation in mitral valve prolapse susceptible gene DCHS1 causes familial mitral annular disjunction J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Nan Zhou, Qianhao Zhao, Rui Li, Ruofei Cheng, Qiuping Wu, Jianding Cheng, Yangxin Chen
Background Mitral annular disjunction (MAD) is an under-recognised phenotype associated with severe ventricular arrhythmias. Limited knowledge has been gained on its molecular genesis. Methods A total of 150 unrelated deceased Chinese were collected for whole-exome sequencing, with analysis focusing on a panel of 118 genes associated with ‘abnormal mitral valve morphology’. Cases were prespecified
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Further delineation of the rare GDACCF (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies syndrome): genotype and phenotype of 22 patients with ZNF148 mutations J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Katalin Szakszon, Charles Marques Lourenco, Bert Louis Callewaert, David Geneviève, Flavien Rouxel, Denis Morin, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Wesley G Patterson, Raymond Louie, Filippo Pinto e Vairo, Eric Klee, Charu Kaiwar, Ralitza H Gavrilova, Katherine E Agre, Sebastien Jacquemont, Jizi Khadijé, Jacques Giltay, Koen van Gassen, Gabriella Merő, Erica Gerkes, Bregje W Van Bon, Tuula
Background Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. Methods As a result of an international collaboration using
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Co-design of patient information leaflets for germline predisposition to cancer: recommendations for clinical practice from the UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar Programme and the Association of Genetic Nurse Counsellors (AGNC) J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Kelly Kohut, Beverley Speight, Julie Young, Rosalind Way, Jennifer Wiggins, Laura Monje-Garcia, Diana M Eccles, Claire Foster, Lesley Turner, Katie Snape, Helen Hanson, on behalf of the CanGene-CanVar Patient Reference Panel
Background Testing for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice
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Integrating a Polygenic Risk Score into a clinical setting would impact risk predictions in familial breast cancer J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Panagiotis Baliakas, Arielle R Munters, Anders Kämpe, Bianca Tesi, Marie-Louise Bondeson, Claes Ladenvall, Daniel Eriksson
Background Low-impact genetic variants identified in population-based genetic studies are not routinely measured as part of clinical genetic testing in familial breast cancer (BC). We studied the consequences of integrating an established Polygenic Risk Score (PRS) (BCAC 313, PRS313) into clinical sequencing of women with familial BC in Sweden. Methods We developed an add-on sequencing panel to capture
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Recurrent BRCA2 exon 3 deletion in Assyrian families J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Rachel Hodan, Kerry Kingham, Allison W Kurian
We identified six patients from five families with a recurrent mutation: NM_000059.3 ( BRCA2 ) exon 3 deletion. All families self-identified as Assyrian. Assyrians are an ethnoreligious population of ancient Mesopotamia, now mostly living in modern day Iraq, Syria, Turkey and Iran. They are historically a socially isolated population with intermarriage within their community, living as a religious
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Neurofibromatosis type 1 mosaicism in patients with constitutional mismatch repair deficiency J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Léa Guerrini-Rousseau, Eric Pasmant, Martine Muleris, Samuel Abbou, Tiphaine Adam-De-Beaumais, Laurence Brugieres, Odile Cabaret, Chrystelle Colas, Sophie Cotteret, Philippe Decq, Christelle Dufour, Erell Guillerm, Etienne Rouleau, Pascale Varlet, Saïma Zili, Dominique Vidaud, Jacques Grill
Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1 ) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated
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Evidence of a genetic background predisposing to complex regional pain syndrome type 1 J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Samiha S Shaikh, Andreas Goebel, Michael C Lee, Michael S Nahorski, Nicholas Shenker, Yunisa Pamela, Ichrak Drissi, Christopher Brown, Gillian Ison, Maliha F Shaikh, Anoop Kuttikat, William A Woods, Abhishek Dixit, Kaitlin Stouffer, Murray CH Clarke, David K Menon, C Geoffrey Woods
Background Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. Methods Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery
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TBX20 loss-of-function variants in families with left ventricular non-compaction cardiomyopathy J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Yuchen Chang, Julie Wacker, Jodie Ingles, Ivan Macciocca, Ingrid King, The Australian Genomics Cardiovascular Disorders Flagship, Christopher Semsarian, Julie McGaughran, Robert G Weintraub, Richard D Bagnall
TBX20 encodes a cardiac transcription factor that is associated with atrial septal defects. Recent studies implicate loss-of-function TBX20 variants with left ventricular non-compaction cardiomyopathy (LVNC), although clinical and genetic data in families are limited. We report four families with TBX20 loss-of-function variants that segregate with LVNC. Genetic testing using genome or exome sequencing
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Changing the standardised obstetric care by expanded carrier screening and counselling: a multicentre prospective cohort study J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Han-Ying Chen, Shin-Yu Lin, Jin-Chung Shih, Jessica Kang, Yi-Yun Tai, Steven W. Shaw, Kuang-Cheng Chen, Kevin Mai, Chien-Nan Lee
Background Expanded genetic screening before conception or during prenatal care can provide a more comprehensive evaluation of heritable fetal diseases. This study aimed to provide a large cohort to evaluate the significance of expanded carrier screening and to consolidate the role of expanded genetic screening in prenatal care. Methods This multicentre, retrospective cohort study was conducted between
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Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of ‘gene-negative’ individuals recruited to the 100 000 Genomes Project J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Claire L Shovlin, Fatma I Almaghlouth, Ali Alsafi, Nicola Coote, Catherine Rennie, Gillian MF Wallace, Fatima S Govani, Genomics England Research Consortium
Hereditary haemorrhagic telangiectasia (HHT) is diagnosed clinically by the Curaçao Criteria of spontaneous recurrent nosebleeds, mucocutaneous telangiectasia at characteristic sites, visceral involvement (arteriovenous malformations (AVMs); gastrointestinal telangiectasia) and family history.1 Early diagnosis is important to enable AVM screening and preventative treatments.2–5 HHT is caused by loss-of-function
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Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Nicole Weisschuh, Pascale Mazzola, Theresia Zuleger, Karin Schaeferhoff, Laura Kühlewein, Friederike Kortüm, Dennis Witt, Alexandra Liebmann, Ruth Falb, Lisa Pohl, Milda Reith, Lara G Stühn, Miriam Bertrand, Amelie Müller, Nicolas Casadei, Olga Kelemen, Carina Kelbsch, Christoph Kernstock, Paul Richter, Francoise Sadler, German Demidov, Leon Schütz, Jakob Admard, Marc Sturm, Ute Grasshoff, Felix Tonagel
Purpose Genome sequencing (GS) is expected to reduce the diagnostic gap in rare disease genetics. We aimed to evaluate a scalable framework for genome-based analyses ‘beyond the exome’ in regular care of patients with inherited retinal degeneration (IRD) or inherited optic neuropathy (ION). Methods PCR-free short-read GS was performed on 1000 consecutive probands with IRD/ION in routine diagnostics
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Association between genetic polymorphisms and risk of adolescent idiopathic scoliosis in case-control studies: a systematic review J. Med. Genet. (IF 4.0) Pub Date : 2024-02-01 Elizabeth Terhune, Patricia Heyn, Christi Piper, Cambria Wethey, Anna Monley, Melissa Cuevas, Nancy Hadley Miller
Background Adolescent idiopathic scoliosis (AIS) is a structural lateral spinal curvature of ≥10° with rotation. Approximately 2%–3% of children across populations are affected with AIS, and this condition is responsible for ~$3 billion in costs within the USA. Although AIS is believed to have a strong genetic contribution, clinical translation of identified genetic variants has stalled. Methods The
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GRN mutation spectrum and genotype–phenotype correlation in Chinese dementia patients: data from PUMCH dementia cohort J. Med. Genet. (IF 4.0) Pub Date : 2024-01-16 Caiyan Liu, Liling Dong, Jie Wang, Jie Li, Xinying Huang, Dan Lei, Chenhui Mao, Shanshan Chu, Longze Sha, Qi Xu, Bin Peng, Liying Cui, Jing Gao
Methods The GRN mutations, especially of the loss of function type, are causative of frontotemporal dementia (FTD). However, several GRN variants can be found in other neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease. So far, there have been over 300 GRN mutations reported globally. However, the genetic spectrum and phenotypic characteristics have not been fully
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Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum J. Med. Genet. (IF 4.0) Pub Date : 2024-01-16 Ken Higashimoto, Feifei Sun, Eri Imagawa, Ken Saida, Noriko Miyake, Satoshi Hara, Hitomi Yatsuki, Musashi Kubiura-Ichimaru, Atsushi Fujita, Takeshi Mizuguchi, Naomichi Matsumoto, Hidenobu Soejima
Background Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations at 11p15. Because approximately 20% of patients test negative via molecular testing of peripheral blood leukocytes, the concept of Beckwith-Wiedemann spectrum (BWSp) was established to encompass a broader cohort with diverse and overlapping phenotypes. The prevalence of other overgrowth syndromes
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Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank J. Med. Genet. (IF 4.0) Pub Date : 2024-01-08 Francesco Casanova, Qu Tian, Janice L Atkins, Andrew R Wood, Daniel Williamson, Yong Qian, David Zweibaum, Jun Ding, David Melzer, Luigi Ferrucci, Luke C Pilling
Background Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. Methods We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic
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Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2 J. Med. Genet. (IF 4.0) Pub Date : 2023-12-30 Giovanni Innella, Simona Ferrari, Sara Miccoli, Elena Luppi, Cristina Fortuno, Michael T Parsons, Amanda B Spurdle, Daniela Turchetti
Background BRCA1/2 testing is crucial to guide clinical decisions in patients with hereditary breast/ovarian cancer, but detection of variants of uncertain significance (VUSs) prevents proper management of carriers. The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) BRCA1/2 Variant Curation Expert Panel (VCEP) has recently developed BRCA1/2 variant classification
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Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers J. Med. Genet. (IF 4.0) Pub Date : 2023-12-30 Jesús Piqueras-Flores, Eduardo Villacorta-Argüelles, Joseph Galvin, Vicente Climent-Payá, Luis Enrique Escobar-López, Almudena Amor-Salamanca, Soledad Garcia-Hernandez, Sean Esmonde, Jorge Martínez-Del Río, Maeve Soto-Pérez, Pablo Garcia-Pavia, Juan Pablo Ochoa
Formin homology 2 domain-containing 3 ( FHOD3 ) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3
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Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey J. Med. Genet. (IF 4.0) Pub Date : 2023-12-22 Sophie Allen, Lucy Loong, Alice Garrett, Bethany Torr, Miranda Durkie, James Drummond, Alison Callaway, Rachel Robinson, George J Burghel, Helen Hanson, Joanne Field, Trudi McDevitt, Terri P McVeigh, Tina Bedenham, Christopher Bowles, Kirsty Bradshaw, Claire Brooks, Samantha Butler, Juan Carlos Del Rey Jimenez, Lorraine Hawkes, Victoria Stinton, Suzanne MacMahon, Martina Owens, Sheila Palmer-Smith
Background National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002–2023) submitted to the National Disease Registration Service revealed heterogeneity across
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Breast cancer risk in NF1-deleted patients J. Med. Genet. (IF 4.0) Pub Date : 2023-12-22 Laurence Pacot, Julien Masliah-Planchon, Adina Petcu, Benoit Terris, Marion Gauthier Villars, James Lespinasse, Pierre Wolkenstein, Anne Vincent-Salomon, Dominique Vidaud, Eric Pasmant
Neurofibromatosis type 1 (NF1, OMIM #162200) is a genetic condition with an autosomal dominant transmission. The disorder is caused by loss-of-function variants in NF1 . The tumour suppressor gene NF1 (OMIM *613113) encodes neurofibromin, a negative regulator of the RAS-mitogen-activated protein kinase (MAPK) pathway. NF1 is associated with an increased risk of developing malignant tumours, mainly
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Carriers of autosomal recessive conditions: are they really ‘unaffected?’ J. Med. Genet. (IF 4.0) Pub Date : 2024-01-01 Amber Hames, Sophia Khan, Clara Gilliland, Lucy Goldman, Hillary WH Lo, Kevin Magda, Justine Keathley
Mendel’s Law of Dominance suggests that recessive disease expression requires the inheritance of two mutated alleles as the dominant, wildtype allele suppresses disease presentation leading to the expression of physiological normal phenotypes. However, there is existing evidence that challenges this school of thought. Here, we summarise existing literature evaluating metabolic and health impacts among
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Evaluation of the clinical, biochemical, genotype and prognosis of mut-type methylmalonic acidemia in 365 Chinese cases J. Med. Genet. (IF 4.0) Pub Date : 2024-01-01 Lili Liang, Shiying Ling, Yue Yu, Ruixue Shuai, Wenjuan Qiu, Huiwen Zhang, Linghua Shen, Shengnan Wu, Haiyan Wei, Yongxing Chen, Chiju Yang, Peng Xu, Xigui Chen, Hui Zou, Jizhen Feng, Tingting Niu, Haili Hu, Zhuwen Gong, Ting Chen, Xia Zhan, Xuefan Gu, Lianshu Han
Background Methylmalonic acidemia (MMA), which results from defects in methylmalonyl-CoA mutase ( mut type) or its cofactor, is the most common inherited organic acid metabolic disease in China. This study aimed to investigate the phenotype and genotype of mut -type MMA in Chinese patients. Methods We recruited 365 patients with mut -type MMA; investigated their disease onset, newborn screening (NBS)