Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1
In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13. In the third family, long ...
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Pagnamenta, A. T., Yu, J., Evans, J., Twiss, P., Genomics England Research Consortium, Musculoskeletal GeCIP MDT, Offiah, A. C., Wafik, M., Mehta, S. G., Javaid, M. K., Smithson, S. F., Taylor, J. C., Ambrose, Arumugam, Bevers, Bleda, Boardman-Pretty, Bou Tags: Open access Structural variation Source Type: research
Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia
Conclusion
We confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in CBFB in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Beyltjens, T., Boudin, E., Revencu, N., Boeckx, N., Bertrand, M., Schütz, L., Haack, T. B., Weber, A., Biliouri, E., Vinksel, M., Zagozen, A., Peterlin, B., Pai, S., Telegrafi, A., Henderson, L. B., Ells, C., Turner, L., Wuyts, W., Van Hul, W., He Tags: Open access Novel disease loci Source Type: research
Recurrent 17q12 microduplications contribute to renal disease but not diabetes
Conclusion
We demonstrate 17q12 microdeletions but not microduplications are associated with diabetes in a population-based cohort, likely caused by HNF1B haploinsufficiency. We show that both 17q12 microdeletions and microduplications are associated with renal disease, and multiple genes within the region likely contribute to renal and neurocognitive phenotypes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Cannon, S., Clissold, R., Sukcharoen, K., Tuke, M., Hawkes, G., Beaumont, R. N., Wood, A. R., Gilchrist, M., Hattersley, A. T., Oram, R. A., Patel, K., Wright, C., Weedon, M. N. Tags: Open access Copy-number variation Source Type: research
Identifying the molecular drivers of ALS-implicated missense mutations
Conclusion
Using our three genes as case studies, we identified distinct insights which can drive further research to better understand ALS. The information curated in our database can serve as a resource for similar gene-specific analyses, further improving the current understanding of disease, crucial for the development of treatment strategies. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Portelli, S., Albanaz, A., Pires, D. E. V., Ascher, D. B. Tags: Genotype-phenotype correlations Source Type: research
Genotype-phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions
Conclusion
The number of generations and the status of exon 2 could affect age of onset of VHL-related manifestations. Onset age was an independent risk factor for overall survival. TKI therapy was effective in VHL patients with LDs. Our findings would further support clinical surveillance and decision-making processes. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Zhang, K., Yang, W., Ma, K., Qiu, J., Li, L., Xu, Y., Zhang, Z., Yu, C., Zhou, J., Gong, Y., Cai, L., Gong, K. Tags: Genotype-phenotype correlations Source Type: research
Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis
Conclusion
Here we present a general mechanism how deletions, duplications or inversions at the NR0B1 locus can lead to partial or complete GD by disrupting the cognate TAD in the vicinity of NR0B1. This model not only allows better diagnosis of GD with copy number variations (CNVs) at Xp21.2, but also gives deeper insight on how spatiotemporal activation of developmental genes can be disrupted by reorganised TADs causing impairment of gonadal development. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Meinel, J. A., Yumiceba, V., Künstner, A., Schultz, K., Kruse, N., Kaiser, F. J., Holterhus, P.-M., Claviez, A., Hiort, O., Busch, H., Spielmann, M., Werner, R. Tags: Open access Chromosomal rearrangements Source Type: research
Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants in SMAD4: a nationwide study
Conclusion
We present a nationwide study of one of the largest populations of patients with PVs in SMAD4 that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curacao criteria. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Jelsig, A. M., Kjeldsen, A., Christensen, L. L., Bertelsen, B., Karstensen, J. G., Brusgaard, K., Torring, P. M. Tags: Phenotypes Source Type: research
APC germline pathogenic variants and epithelial ovarian cancer: causal or coincidental findings?
APC germline pathogenic variants result in predisposition to familial adenomatous polyposis and extraintestinal tumours such as desmoid fibromatosis, medulloblastomas and thyroid cancers. They have also been recently involved in ovarian microcystic stromal tumours. APC inactivation has been described at the tumour level in epithelial ovarian cancers (EOCs). Here, we report the identification of APC germline pathogenic variants in two patients diagnosed with premenopausal EOC in early 30s, with no other pathogenic variant detected in the known ovarian cancer predisposing genes. Subsequent tumour analysis showed neither a se...
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Vibert, R., Le Gall, J., Buecher, B., Mouret-Fourme, E., Bataillon, G., Becette, V., Trabelsi-Grati, O., Moncoutier, V., Dehainault, C., Carriere, J., Schwartz, M., Suybeng, V., Bieche, I., Colas, C., Vincent-Salomon, A., Stoppa-Lyonnet, D., Golmard, L. Tags: Cancer genetics Source Type: research
Comprehensive RNA and protein functional assessments contribute to the clinical interpretation of MSH2 variants causing in-frame splicing alterations
Conclusion
Altogether, these data demonstrate that MSH2 function is intolerant to in-frame indels caused by the spliceogenic variants analysed in this study, supporting their pathogenic nature. This work stresses the importance of combining complementary RNA and protein approaches to ensure accurate clinical interpretation of in-frame spliceogenic variants. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Meulemans, L., Baert Desurmont, S., Waill, M.-C., Castelain, G., Killian, A., Hauchard, J., Frebourg, T., Coulet, F., Martins, A., Muleris, M., Gaildrat, P. Tags: Cancer genetics Source Type: research
The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2
Conclusion
OC surveillance for women deferring RRSO in a ‘real-world’ setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Philpott, S., Raikou, M., Manchanda, R., Lockley, M., Singh, N., Scott, M., Evans, D. G., Adlard, J., Ahmed, M., Edmondson, R., Woodward, E. R., Lamnisos, A., Balega, J., Brady, A. F., Sharma, A., Izatt, L., Kulkarni, A., Tripathi, V., Solomons, J. S., Ha Tags: Open access, Press releases Cancer genetics Source Type: research
Long-term outcomes of very early treated infantile-onset Pompe disease with short-term steroid premedication: experiences from a nationwide newborn screening programme
Conclusion
Very early ERT using our rapid diagnostic and treatment strategy enabled our patients with IOPD to have better outcomes than patients in other medical centres. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Yang, C.-F., Liao, T.-W. E., Chu, Y.-L., Chen, L.-Z., Huang, L.-Y., Yang, T.-F., Ho, H.-C., Kao, S.-M., Niu, D.-M. Tags: Biochemical genetics Source Type: research
UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2
Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1, BRCA2, MLH1, MSH2, MSH6, BRIP1, PALB2, RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1, BRCA2, MLH1, MSH2 and MSH6, there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1, PALB2, RAD51D and RAD51C, with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and RAD51D as OC predis...
Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Hanson, H., Kulkarni, A., Loong, L., Kavanaugh, G., Torr, B., Allen, S., Ahmed, M., Antoniou, A. C., Cleaver, R., Dabir, T., Evans, D. G., Golightly, E., Jewell, R., Kohut, K., Manchanda, R., Murray, A., Murray, J., Ong, K.-R., Rosenthal, A. N., Woodward, Tags: Open access Position statement Source Type: research
Correction: Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome
Sarkozy A, Conti E, Digilio MC, et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet 2004;41:e68. doi: 10.1136/jmg.2003.013466.
In the original article, an error in the Results section was identified and upon re-examination, this correction notice is being issued to note that PTPN11 c.1492C>T variant results in p.Arg498Trp and not in p.Arg498Leu, and c.1493G>T variant results in p.Arg498Leu. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 20, 2023 Category: Genetics & Stem Cells Tags: Miscellaneous Source Type: research
Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
Conclusion
A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 20, 2023 Category: Genetics & Stem Cells Authors: Castilla-Vallmanya, L., Centeno-Pla, M., Serrano, M., Franco-Valls, H., Martinez-Cabrera, R., Prat-Planas, A., Rojano, E., Ranea, J. A. G., Seoane, P., Oliva, C., Paredes-Fuentes, A. J., Marfany, G., Artuch, R., Grinberg, D., Rabionet, R., Balcells, S., U Tags: Open access Functional genomics Source Type: research
A founder UMOD variant is a common cause of hereditary nephropathy in the British population
Conclusion
Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 20, 2023 Category: Genetics & Stem Cells Authors: Valluru, M. K., Chung, N. K., Gilchrist, M., Butland, L., Cook, J., Takou, A., Dixit, A., Weedon, M. N., Ong, A. C. M., The Genomics England Research Consortium, Ambrose, Arumugam, Bevers, Bleda, Boardman-Pretty, Boustred, Brittain, Caulfield, Chan, Elgar Tags: Open access Population genetics Source Type: research
