A polymorphic AT-repeat causes frequent allele dropout for an MME mutational hotspot exon
Pathogenic variants in the MME gene cause dominant and recessive late-onset axonal hereditary neuropathy, that is, axonal Charcot-Marie-Tooth syndrome (LOCMT2). Here, we report next-generation sequencing (NGS) and Sanger sequencing (SS) results of 28 LOCMT2 patients carrying either the repeatedly reported c.467del p.(Pro156Leufs*14) or the c.440–2A>C variants. We demonstrate that an intronic AT-repeat in close proximity to these two mutations is frequently causing an allele dropout during SS that result in false genotyping in a considerable proportion of patients. This may result in an incorrect diagnosis, which h...
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Hoyer, H., Hilmarsen, H. T., Sunder-Plassmann, R., Braathen, G. J., Andersen, P. M., Beetz, C., Hacker, S., Holla, O. L., Kurth, I., Löscher, W. N., Reiter, S. B. C. F., Rudnik-Schöneborn, S., Strand, L., Windhager, R., Witsch-Baumgartner, Tags: Open access Diagnostics Source Type: research
Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?
Conclusions
Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Garcia, B., Catasus, N., Ros, A., Rosas, I., Negro, A., Guerrero-Murillo, M., Valero, A. M., Duat-Rodriguez, A., Becerra, J. L., Bonache, S., Lazaro Garcia, C., Comas, C., Bielsa, I., Serra, E., Hernandez-Chico, C., Martin, Y., Castellanos, E., Blanco, I. Tags: Diagnostics Source Type: research
RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders
Conclusion
RNA splicing analysis is an important method to assess the impact of sequence variants on splicing in clinical practice and can contribute to the reclassification of a significant proportion of VUSs. RNA splicing analysis should be considered for genetic disease diagnostics. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: He, W.-B., Xiao, W.-J., Dai, C.-L., Wang, Y.-R., Li, X.-R., Gong, F., Meng, L.-L., Tan, C., Zeng, S.-C., Lu, G.-X., Lin, G., Tan, Y.-Q., Hu, H., Du, J. Tags: Diagnostics Source Type: research
Multimodal bioinformatic analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles
Conclusions
TECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer’s disease and Huntington’s disease. Specifically, we speculate that TECPR2 plays an important role as a proteostasis regulator during synaptogenesis, highlighting its importance in developing neurons. By advancing our understanding of TECPR2 function, this work provides an essential stepping stone towards the development of precision diagnostics and targeted treatment options for TECPR2-related disorders. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Shalev, I., Somekh, J., Eran, A. Tags: Functional genomics Source Type: research
A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene
Conclusion
We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Bertoli-Avella, A., Hotakainen, R., Al Shehhi, M., Urzi, A., Pareira, C., Marais, A., Al Shidhani, K., Aloraimi, S., Morales-Torres, G., Fisher, S., Demuth, L., Moteleb Selim, L. A., Al Menabawy, N., Busehail, M., AlShaikh, M., Gilani, N., Chalabi, D. N., Tags: Open access Novel disease loci Source Type: research
Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy
Conclusions
Our study demonstrates for the first time that the variants in the S6K1 gene are associated with HCM, and early detection of the S6K1 variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of S6K1 gene variants. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Jain, P. K., Jayappa, S., Sairam, T., Mittal, A., Paul, S., Rao, V. J., Chittora, H., Kashyap, D. K., Palakodeti, D., Thangaraj, K., Shenthar, J., Koranchery, R., Rajendran, R., Alireza, H., Mohanan, K. S., Rathinavel, A., Dhandapany, P. S. Tags: Novel disease loci Source Type: research
Constitutional chromothripsis of the APC locus as a cause of genetic predisposition to colon cancer
Conclusions
Based on comprehensive genomic analysis, we propose that constitutional chromothripsis dampening APC expression, possibly modified by additional APC–Axin–GSK3B–β-catenin pathway disruptions, underlies the patient’s clinical phenotype. The combinatorial approach we deployed provides a powerful tool set for deciphering unsolved familial polyposis and potentially other tumour syndromes and monogenic diseases. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Scharf, F., Leal Silva, R. M., Morak, M., Hastie, A., Pickl, J. M. A., Sendelbach, K., Gebhard, C., Locher, M., Laner, A., Steinke-Lange, V., Koehler, U., Holinski-Feder, E., Wolf, D. A. Tags: Open access Chromosomal rearrangements Source Type: research
De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability
Conclusion
Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Schalk, A., Cousin, M. A., Dsouza, N. R., Challman, T. D., Wain, K. E., Powis, Z., Minks, K., Trimouille, A., Lasseaux, E., Lacombe, D., Angelini, C., Michaud, V., Van-Gils, J., Spataro, N., Ruiz, A., Gabau, E., Stolerman, E., Washington, C., Louie, R., L Tags: Cognitive and behavioural genetics Source Type: research
Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency
Conclusion
Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Verheyen, S., Blatterer, J., Speicher, M. R., Bhavani, G. S., Boons, G.-J., Ilse, M.-B., Andrae, D., Spross, J., Vaz, F. M., Kircher, S. G., Posch-Pertl, L., Baumgartner, D., Lübke, T., Shah, H., Al Kaissi, A., Girisha, K. M., Plecko, B. Tags: Open access Biochemical genetics Source Type: research
Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients
Conclusion
This study indicated that affected offspring of VHL patients with CNS as the first presenting symptom was an independent risk factor for overall survival and CHB-specific survival. Generation and mutation region only had an effect on the onset age, which is helpful to clinical decision-making and generate a more precise surveillance protocol. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Zhang, K., Qiu, J., Yang, W., Ma, K., Li, L., Xie, H., Xu, Y., Gong, Y., Zhou, J., Cai, L., Gong, K. Tags: Open access Genotype-phenotype correlations Source Type: research
Variable skeletal phenotypes associated with biallelic variants in PRKG2
The 100 000 Genomes Project (100KGP) is a UK-wide initiative that has a goal of using whole genome sequencing (WGS) to identify genetic causes of rare inherited diseases and embed the use of this technology within the NHS.1 Using data from this resource alongside international gene-matching efforts, four individuals from two independent families were identified harbouring homozygous frameshift or stop-gain variants in PRKG2, a recently described skeletal dysplasia gene.2 Detailed clinical and radiological assessments helped extend the phenotypic range associated with this autosomal recessive condition while functional stud...
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Pagnamenta, A. T., Diaz-Gonzalez, F., Banos-Pinero, B., Ferla, M. P., Toosi, M. B., Calder, A. D., Karimiani, E. G., Doosti, M., Wainwright, A., Wordsworth, P., Bailey, K., Ejeskär, K., Lester, T., Maroofian, R., Heath, K. E., Tajsharghi, H., Shea Tags: Open access Genotype-phenotype correlations Source Type: research
Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-{beta}-opathies with craniofacial manifestations using an innovative multimodality method
Conclusions
This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-β signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-β pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Almpani, K., Liberton, D. K., Jani, P., Keyvanfar, C., Mishra, R., Curry, N., Orzechowski, P., Frischmeyer-Guerrerio, P. A., Lee, J. S. Tags: Open access Genotype-phenotype correlations Source Type: research
Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists
Purpose and scope
The aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems.
Methods of statement development
A multidisciplinary group was assembled to review existing literature on fetal GWS for genetic di...
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Lazier, J., Hartley, T., Brock, J.-A., Caluseriu, O., Chitayat, D., Laberge, A.-M., Langlois, S., Lauzon, J., Nelson, T. N., Parboosingh, J., Stavropoulos, D. J., Boycott, K., Armour, C. M., On behalf of the Canadian College of Medical Geneticists Tags: Open access Position statement Source Type: research
Swiss cost-effectiveness analysis of universal screening for Lynch syndrome of patients with colorectal cancer followed by cascade genetic testing of relatives
Conclusion
Results can inform policymakers, healthcare providers and insurance companies about the costs and benefits associated with universal screening for LS and cascade genetic testing of relatives. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Salikhanov, I., Heinimann, K., Chappuis, P., Buerki, N., Graffeo, R., Heinzelmann, V., Rabaglio, M., Taborelli, M., Wieser, S., Katapodi, M. C. Tags: Open access Screening Source Type: research
Sporadic facial angiofibroma and sporadic angiomyolipoma mimicking tuberous sclerosis complex
In this report, we describe an individual with minimal TSC clinical features, who had ‘no mutation identified’ (NMI) by prior genetic testing in a clinical laboratory. Our massively parallel sequencing (MPS) analysis of multiple samples from different body sites and tumours (including blood, saliva, normal skin, AML and FAF) revealed an extraordinary situation in which FAF and AML had completely independent inactivating biallelic variants in TSC2, not present in other matched samples. This suggests that the two different lesions (AML and FAF) are not due to the same underlying germline or mosaic mutation, rathe...
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Klonowska, K., Thiele, E. A., Grevelink, J. M., Thorner, A. R., Kwiatkowski, D. J. Tags: Somatic mosaicism Source Type: research
