Uncovering the burden of hidden ciliopathies in the 100 000 Genomes Project: a reverse phenotyping approach
Conclusion
Reverse phenotyping improves the rate of successful molecular diagnosis for unsolved 100K participants with primary ciliopathies. Previous analyses likely missed these diagnoses because incomplete HPO term entry led to incorrect gene panel choice, meaning that pathogenic variants were not prioritised. Better phenotyping data are therefore essential for accurate variant interpretation and improved patient benefit. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - November 22, 2022 Category: Genetics & Stem Cells Authors: Best, S., Yu, J., Lord, J., Roche, M., Watson, C. M., Bevers, R. P. J., Stuckey, A., Madhusudhan, S., Jewell, R., Sisodiya, S. M., Lin, S., Turner, S., Robinson, H., Leslie, J. S., Baple, E., Genomics England Research Consortium, Toomes, C., Inglehearn, C Tags: Open access Developmental defects Source Type: research
Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/{beta}-catenin pathway
Conclusion
Our results suggest that R225Q variant is associated with increased susceptibility to DCM. Ageing could enhance this process via activating WNT/β-catenin signaling in response to increased intracellular pH. Antagonising the WNT/β-catenin pathway might be a potential therapeutic strategy for mitigating R225Q variant-related DCM pathogenesis. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - November 22, 2022 Category: Genetics & Stem Cells Authors: Hu, J., Yang, K., Zhao, Y., Wei, Z., Yang, L., Gao, R., Wu, Y., Xu, L., Xu, S., Hu, K., Sun, A., Ge, J. Tags: Genotype-phenotype correlations Source Type: research
Likely pathogenic structural variants in genetically unsolved patients with retinitis pigmentosa revealed by long-read sequencing
Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with...
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Sano, Y., Koyanagi, Y., Wong, J. H., Murakami, Y., Fujiwara, K., Endo, M., Aoi, T., Hashimoto, K., Nakazawa, T., Wada, Y., Ueno, S., Gao, D., Murakami, A., Hotta, Y., Ikeda, Y., Nishiguchi, K. M., Momozawa, Y., Sonoda, K.-H., Akiyama, M., Fujimoto, A. Tags: Open access Structural variation Source Type: research
Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group
Conclusion
Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Guerrini-Rousseau, L., Masliah-Planchon, J., Waszak, S. M., Alhopuro, P., Benusiglio, P. R., Bourdeaut, F., Brecht, I. B., Del Baldo, G., Dhanda, S. K., Garre, M. L., Gidding, C. E. M., Hirsch, S., Hoarau, P., Jorgensen, M., Kratz, C., Lafay-Cousin, L., M Tags: Open access Cancer genetics Source Type: research
Novel POLE mutations identified in patients with IMAGE-I syndrome cause aberrant subcellular localisation and protein degradation in the nucleus
Conclusion
These findings provide new insights regarding the mechanism via which POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression, a characteristic of DNA replisome-associated diseases. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Nakano, T., Sasahara, Y., Kikuchi, A., Moriya, K., Niizuma, H., Niihori, T., Shirota, M., Funayama, R., Nakayama, K., Aoki, Y., Kure, S. Tags: Open access Immunogenetics Source Type: research
Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation
Conclusion
The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Shimada, S., Ng, B. G., White, A. L., Nickander, K. K., Turgeon, C., Liedtke, K. L., Lam, C. T., Font-Montgomery, E., Lourenco, C. M., He, M., Peck, D. S., Umana, L. A., Uhles, C. L., Haynes, D., Wheeler, P. G., Bamshad, M. J., Nickerson, D. A., Cushing, Tags: Phenotypes Source Type: research
Identifying the psychosocial predictors of ultraviolet exposure to the face in patients with xeroderma pigmentosum: a study of the behavioural factors affecting clinical outcomes in this genetic disease
Conclusions
We have identified factors contributing to poor photoprotection in XP. Identifying these potentially reversible psychosocial features has enabled us to design an intervention to improve photoprotection in patients with XP, aiming to prevent skin and eye cancers in these patients. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Sarkany, R., Norton, S., Canfield, M., Morgan, M., Foster, L., Sainsbury, K., Araujo-Soares, V., Wulf, H. C., Weinman, J., Walburn, J. Tags: Open access Cognitive and behavioural genetics Source Type: research
Targeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases
Conclusion
T-LRS is an effective method for identifying missing pathogenic variants. Although limitations with computational prediction algorithms can hinder the interpretation of variants, T-LRS is particularly effective in identifying intronic variants. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Miller, D. E., Lee, L., Galey, M., Kandhaya-Pillai, R., Tischkowitz, M., Amalnath, D., Vithlani, A., Yokote, K., Kato, H., Maezawa, Y., Takada-Watanabe, A., Takemoto, M., Martin, G. M., Eichler, E. E., Hisama, F. M., Oshima, J. Tags: Open access Diagnostics Source Type: research
Long-read sequencing to resolve the parent of origin of a de novo pathogenic UBE3A variant
Conclusion
Long-read nanopore sequencing provides significant clinical utility when assessing the parental origin of de novo variants. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Watson, C. M., Jackson, L., Crinnion, L. A., Bonthron, D. T., Sheridan, E. Tags: Diagnostics Source Type: research
Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases
Conclusion
The RNA-Seq-based diagnosis of NMDs achieves an increased diagnostic rate and provided pathogenic status information, which is not easily accessible through exome analysis. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Hong, S. E., Kneissl, J., Cho, A., Kim, M. J., Park, S., Lee, J., Woo, S., Kim, S., Kim, J.-S., Kim, S. Y., Jung, S., Kim, J., Shin, J.-Y., Chae, J.-H., Choi, M. Tags: Open access Diagnostics Source Type: research
FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum
Conclusion
FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype–phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Mroczek, M., Longman, C., Farrugia, M. E., Kapetanovic Garcia, S., Ardicli, D., Topaloglu, H., Hernandez-Lain, A., Orhan, D., Alikasifoglu, M., Duff, J., Specht, S., Nowak, K., Ravenscroft, G., Chao, K., Valivullah, Z., Donkervoort, S., Saade, D., Bo Tags: Neurogenetics Source Type: research
Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome
Conclusion
These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Angelozzi, M., Karvande, A., Molin, A. N., Ritter, A. L., Leonard, J. M. M., Savatt, J. M., Douglass, K., Myers, S. M., Grippa, M., Tolchin, D., Zackai, E., Donoghue, S., Hurst, A. C. E., Descartes, M., Smith, K., Velasco, D., Schmanski, A., Crunk, A., To Tags: Neurogenetics Source Type: research
Complete loss of the X-linked gene CASK causes severe cerebellar degeneration
Conclusion
We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Patel, P. A., Hegert, J. V., Cristian, I., Kerr, A., LaConte, L. E. W., Fox, M. A., Srivastava, S., Mukherjee, K. Tags: Neurogenetics Source Type: research
Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis
Conclusion
Our study is in line with previous observations made in the mouse showing that SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. Consistent with an enteric form of hyperoxaluria, we observed a beneficial effect of increasing calcium in the patient’s diet to reduce urinary oxalate excretion. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - October 21, 2022 Category: Genetics & Stem Cells Authors: Corniere, N., Thomson, R. B., Thauvin, S., Villoutreix, B. O., Karp, S., Dynia, D. W., Burlein, S., Brinkmann, L., Badreddine, A., Dechaume, A., Derhourhi, M., Durand, E., Vaillant, E., Froguel, P., Chambrey, R., Aronson, P. S., Bonnefond, A., Eladari, D. Tags: Open access Novel disease loci Source Type: research
DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Lebers hereditary optic neuropathy and optic atrophy
Conclusion
This study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - September 26, 2022 Category: Genetics & Stem Cells Authors: Kieninger, S., Xiao, T., Weisschuh, N., Kohl, S., Rüther, K., Kroisel, P. M., Brockmann, T., Knappe, S., Kellner, U., Lagreze, W., Mazzola, P., Haack, T. B., Wissinger, B., Tonagel, F. Tags: Open access Vision science Source Type: research
