Extent of investigation and management of cases of 'unexplained mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus
JMG - Genetics Recent issues
by McVeigh, T. P., Monahan, K. J., Christopher, J., West, N., Scott, M., Murray, J., Hanson, H., UKCGG dMMR Consensus Meeting Attendees, Armstrong, Beggs, Berlin, Boyde, Brady, Bulmer, Burghel, Burn, Catherwood, Christopher, Cleaver, Coad, Conti, Cook, Cope, Corbett, Crosbie, Davidson, DeSouza, Donaldson, Durkie, Eccles, Foot, Frayling, George, Gerrard, Gibson, Green, Greville-Heygate, Hamilton, Hanson, Hart, Hodgson, Holliday, Hoyle, Jewell, Kemp, Kiely, Kiesel, Kohut, Kristeleit, Kumar, Lalloo, Latchford, Lee, Lobo, Loughrey, MacMahon, Martin, Martin, McVeigh, Miedzybrodzka, Minshall, Monahan, Monje-Garcia, Morgan, Mugalaasi, Murray, Musgrave, Nastali, Norbury, Ong, Onyeador, Pagan, Quigley, Ratsma, Rea, Repana, Rosenthal, Scott, Searle, Shaw, Side, Simon, Smith, Solomons, Varde, West, Wiggins, Wren, Yarram-Smith
3w ago
Background Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term ‘Lynch-like syndrome’ (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingl ..read more
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BRCA awareness and testing experience in the UK Jewish population: a qualitative study
JMG - Genetics Recent issues
by Sarig, K., Oxley, S., Kalra, A., Sobocan, M., Fierheller, C. T., Sideris, M., Gootzen, T., Ferris, M., Eeles, R. A., Evans, D. G., Quaife, S. L., Manchanda, R.
3w ago
Background 1 in 40 UK Jewish individuals carry a pathogenic variant in BRCA1/BRCA2. Traditional testing criteria miss half of carriers, and so population genetic testing is being piloted for Jewish people in England. There has been no qualitative research into the factors influencing BRCA awareness and testing experience in this group. This study aimed to explore these and inform improvements for the implementation of population genetic testing. Methods Qualitative study of UK Jewish adults who have undergone BRCA testing. We conducted one-to-one semistructured interviews via telephone or vide ..read more
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Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability
JMG - Genetics Recent issues
by Smith, C. E. L., Laugel-Haushalter, V., Hany, U., Best, S., Taylor, R. L., Poulter, J. A., Wortmann, S. B., Feichtinger, R. G., Mayr, J. A., Al Bahlani, S., Nikolopoulos, G., Rigby, A., Black, G. C., Watson, C. M., Mansour, S., Inglehearn, C. F., Mighell, A. J., Bloch-Zupan, A., The UK Inherited Retinal Disease Consortium, Genomics England Research Consortium, McKibbin, Ali, Toomes, Ingram, Manson, Sergouniotis, Arno, Hardcastle, Webster, Pontikos, Cheetham, Fiorentino, Downes, Yu, Halford, Broadgate, Heyningen, Ambrose, Arumugam, Bevers, Bleda, Boardman-Pretty, Boustred, Brittain, Brown, Caulfield, Chan, Giess, Griffin, Hamblin, Henderson, Hubbard, Jackson, Jones, Kasperaviciute, Kayikci, Kousathanas, Lahnstein, Lakey, Leigh, Leong, Lopez, Maleady-Crowe, McEntagart, Minneci, Mitchell, Moutsianas, Mueller, Murugaesu, Need, O'Donovan, Odhams, Patch, Perez-Gil, Pereira, Pullinger, Rahim, Rendon, Rogers, Savage, Sawant, Scott, Siddiq, Sieghart, Smith, Sosinsky, Stuckey, Tanguy, Taylor Tavares, Thomas, Thompson, Tucci, Welland, Williams, Witkowska, Wood, Zarowiecki
3w ago
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 associated with Mendelian genetic disease. Methods Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imper ..read more
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Exome sequencing of 1190 non-syndromic clubfoot cases reveals HOXD12 as a novel disease gene
JMG - Genetics Recent issues
by Charng, W.-L., Nikolov, M., Shrestha, I., Seeley, M. A., Josyula, N. S., Justice, A. E., Dobbs, M. B., Gurnett, C. A.
3w ago
Background Clubfoot, presenting as a rigid inward and downward turning of the foot, is one of the most common congenital musculoskeletal anomalies. The aetiology of clubfoot is poorly understood and variants in known clubfoot disease genes account for only a small portion of the heritability. Methods Exome sequence data were generated from 1190 non-syndromic clubfoot cases and their family members from multiple ethnicities. Ultra-rare variant burden analysis was performed comparing 857 unrelated clubfoot cases with European ancestry with two independent ethnicity-matched control groups (1043 i ..read more
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Rare variant association analyses reveal the significant contribution of carbohydrate metabolic disturbance in severe adolescent idiopathic scoliosis
JMG - Genetics Recent issues
by Wen, W., Zhao, Z., Zheng, Z., Zhao, S., Zhao, H., Cheng, X., Du, H., Li, Z., Wang, S., Qiu, G., Wu, Z., Zhang, T. J., Wu, N.
3w ago
Background Adolescent idiopathic scoliosis (AIS), the predominant genetic-influenced scoliosis, results in spinal deformities without vertebral malformations. However, the molecular aetiology of AIS remains unclear. Methods Using genome/exome sequencing, we studied 368 patients with severe AIS (Cobb angle >40°) and 3794 controls from a Han Chinese cohort. We performed gene-based and pathway-based weighted rare variant association tests to assess the mutational burden of genes and established biological pathways. Differential expression analysis of muscle tissues from 14 patients with AIS an ..read more
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NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways
JMG - Genetics Recent issues
by Zhang, S., Yang, J., Ji, D., Meng, X., Zhu, C., Zheng, G., Glessner, J., Qu, H.-Q., Cui, Y., Liu, Y., Wang, W., Li, X., Zhang, H., Xiu, Z., Sun, Y., Sun, L., Li, J., Hakonarson, H., Li, J., Xia, Q.
3w ago
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 cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. Results We identified a novel candidate gene N ..read more
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ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes
JMG - Genetics Recent issues
by He, M.-F., Liu, L.-H., Luo, S., Wang, J., Guo, J.-J., Wang, P.-Y., Zhai, Q.-X., He, S.-L., Zou, D.-F., Liu, X.-R., Li, B.-M., Ma, H.-Y., Qiao, J.-D., Zhou, P., He, N., Yi, Y.-H., Liao, W.-P.
3w ago
Background The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. Methods Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. Results Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/sp ..read more
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Survey of service needs to embed genome sequencing for motor neuron disease in neurology in the English National Health Service
JMG - Genetics Recent issues
by Howard, J., Bekker, H. L., McDermott, C. J., McNeill, A.
3w ago
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 skills in English clinicians who see pwMND. There were 245 respondents to the survey (160 neurology clinicians and 85 genetic clinicians). Neurology clinicians reported multiple, overlappi ..read more
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Comparing the frequency of variants of uncertain significance (VUS) between ancestry groups in a paediatric epilepsy cohort
JMG - Genetics Recent issues
by Martin, B. E., Sands, T., Bier, L., Bergner, A., Boehme, A. K., Lippa, N.
3w ago
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 sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR). Me ..read more
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Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis
JMG - Genetics Recent issues
by Altunoglu, U., Palencia-Campos, A., Günes, N., Turgut, G. T., Nevado, J., Lapunzina, P., Valencia, M., Iturrate, A., Otaify, G., Elhossini, R., Ashour, A., K. Amin, A., Elnahas, R. F., Fernandez-Nunez, E., Flores, C.-L., Arias, P., Tenorio, J., Chamorro Fernandez, C. I., Güven, Y., Özsu, E., Eklioglu, B. S., Ibarra-Ramirez, M., Diness, B. R., Burnyte, B., Ajmi, H., Yüksel, Z., Yıldırım, R., Ünal, E., Abdalla, E., Aglan, M., Kayserili, H., Tuysuz, B., Ruiz-Perez, V.
3w ago
Background Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. Methods We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC ..read more
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