BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome
Conclusion
BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Miller, K. A., Cruz Walma, D. A., Pinkas, D. M., Tooze, R. S., Bufton, J. C., Richardson, W., Manning, C. E., Hunt, A. E., Cros, J., Hartill, V., Parker, M. J., McGowan, S. J., Twigg, S. R. F., Chalk, R., Staunton, D., Johnson, D., Wilkie, A. O. M., Bullo Tags: Open access Novel disease loci Source Type: research
Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2
Conclusions
These results demonstrated the effectiveness of new BRCA1/2 ACMG/AMP classification guidelines for VUS classification within a clinical cohort, and their important clinical impact. Furthermore, they suggested a cadence of no more than 3 years for regular review of VUSs, which however requires time, expertise and resources. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Innella, G., Ferrari, S., Miccoli, S., Luppi, E., Fortuno, C., Parsons, M. T., Spurdle, A. B., Turchetti, D. Tags: Cancer genetics Source Type: research
Recontact to return new or updated PALB2 genetic results in the clinical laboratory setting
Conclusion
Novel pathogenic variants in PALB2 were identified in 18 individuals through retrospective gene panel testing. Recontacting these individuals regarding these new or updated findings had a range of outcomes. The process of conveying genomic results within this framework can be effectively accomplished while upholding patient autonomy, potentially leading to advantageous outcomes for patients and their families. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Panchal, S., Mahajan, R., Aujla, N., McKay, P., Casalino, S., Di Gioacchino, V., Charames, G. S., Lefebvre, M., Metcalfe, K. A., Akbari, M. R., McCuaig, J. M., Lerner-Ellis, J. Tags: Cancer genetics Source Type: research
Pathogenic variants affecting the TB5 domain of the fibrillin-1 protein: not only in geleophysic/acromicric dysplasias but also in Marfan syndrome
Conclusion
Surprisingly, pathogenic variants in the TB5 domain of FBN1 can lead to two opposite phenotypes: GPHYSD/ACMICD and MFS, suggesting the existence of different pathogenic sequences with the involvement of tissue specificity. Further functional studies are ongoing to determine the precise role of this domain in the physiopathology of each disease. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Arnaud, P., Mougin, Z., Baujat, G., Drouin-Garraud, V., El Chehadeh, S., Gouya, L., Odent, S., Jondeau, G., Boileau, C., Hanna, N., Le Goff, C. Tags: Open access Diagnostics Source Type: research
Molecular diagnosis, clinical evaluation and phenotypic spectrum of Townes-Brocks syndrome: insights from a large Chinese hearing loss cohort
Conclusion
This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Yan, X., Wang, J., Yang, W., Li, L., Shen, T., Geng, J., Zhang, Q., Zhong, M., Xiong, W., Bu, F., Lu, Y., Zhao, Y., Cheng, J., Yuan, H. Tags: Open access Diagnostics Source Type: research
Improved sensitivity for detection of pathogenic variants in familial NF2-related schwannomatosis
Conclusion
Our study indicates there is added value in performing additional genetic analysis for detection of pathogenic variants that are difficult to identify with current clinical genetic screening methods. In particular, RNA analysis is valuable for accurate classification of non-canonical splicing variants. Karyotype analysis and whole genome sequencing analysis are of particular value for identification of large and/or complex structural variants, with additional advantages in the use of long-read sequencing techniques. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Perez-Becerril, C., Burghel, G. J., Hartley, C., Rowlands, C. F., Evans, D. G., Smith, M. J. Tags: Diagnostics Source Type: research
Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights
Conclusions
Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Atasu, B., Simon-Sanchez, J., Hanagasi, H., Bilgic, B., Hauser, A.-K., Guven, G., Heutink, P., Gasser, T., Lohmann, E. Tags: Open access Neurogenetics Source Type: research
Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank
Discussion
Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E 4. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Casanova, F., Tian, Q., Atkins, J. L., Wood, A. R., Williamson, D., Qian, Y., Zweibaum, D., Ding, J., Melzer, D., Ferrucci, L., Pilling, L. C. Tags: Open access Neurogenetics Source Type: research
Clinical and genetic spectrum of RNF216-related disorder: a new case and literature review
Conclusion
RNF216-related disorder is an inherited neuroendocrine disease characterised by cerebellar ataxia, chorea, cognitive impairment and hypogonadotropic hypogonadism. Most causative variants in patients with RNF216-related disorder influence the RBR domain or C-terminal extension of RNF216. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Wu, C., Zhang, Z. Tags: Neurogenetics Source Type: research
Breast cancer risk in NF1-deleted patients
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 malignant peripheral nerve sheath tumours.1 NF1 women were previously reported to have standardised incidence ratio (SIR) for the development of breast cancer (BC) of 3.5 compared with the general population,2 with an SIR of 11.1 ...
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Pacot, L., Masliah-Planchon, J., Petcu, A., Terris, B., Gauthier Villars, M., Lespinasse, J., Wolkenstein, P., Vincent-Salomon, A., Vidaud, D., Pasmant, E. Tags: Genotype-phenotype correlations Source Type: research
Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers
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 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6....
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Piqueras-Flores, J., Villacorta-Argüelles, E., Galvin, J., Climent-Paya, V., Escobar-Lopez, L. E., Amor-Salamanca, A., Garcia-Hernandez, S., Esmonde, S., Martinez-Del Rio, J., Soto-Perez, M., Garcia-Pavia, P., Ochoa, J. P. Tags: Genotype-phenotype correlations Source Type: research
Childhood-onset hypertrophic cardiomyopathy caused by thin-filament sarcomeric variants
This study describes the natural history and outcomes of children with thin-filament-associated HCM and compares it to thick-filament-associated disease.
Longitudinal data were collected from 40 children under 18 years with a disease-causing variant in a thin-filament protein from a single quaternary referral centre. Twenty-one (female n=6, 35.5%) were diagnosed with HCM at a median age of 13.0 years (IQR 8.3–14.0). Over a median follow-up of 5.0 years (IQR 4.0–8.5), three (14.3%) experienced one or more major adverse cardiac events (MACE) (two patients had an out-of-hospital arrest and eight appropriate implan...
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Norrish, G., Gasparini, M., Field, E., Cervi, E., Kaski, J. P. Tags: Open access Genotype-phenotype correlations Source Type: research
Mosaic RASopathies concept: different skin lesions, same systemic manifestations?
Conclusion
This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic RAS and BRAF pathogenic variants and may help improve their follow-up. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - April 19, 2024 Category: Genetics & Stem Cells Authors: Morren, M.-A., Fodstad, H., Brems, H., Bedoni, N., Guenova, E., Jacot-Guillarmod, M., Busiah, K., Giuliano, F., Gilliet, M., Atallah, I. Tags: Genotype-phenotype correlations Source Type: research
Biallelic PKP2 loss of function variants are associated with a lethal perinatal-onset biventricular dilated cardiomyopathy with excessive trabeculations and ventricular septal defects
We report three more cases from two families with homozygous pathogenic PKP2 variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function PKP2 variants cause a lethal, perinatal-onset cardiomyopathy. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 21, 2024 Category: Genetics & Stem Cells Authors: Gibb, J., Wall, E., Fields, E., Seale, A., Armstrong, C., Bamber, A., Daubeney, P., Jacobs-Pearson, M., Marton, T., Stals, K., Low, K., Kaski, J. P., Spentzou, G. Tags: Phenotypes Source Type: research
Clinical phenotype of FOXP1 syndrome: parent-reported medical signs and symptoms in 40 individuals
Conclusion
The results of this study may be used to further guide medical management and identify patient priorities for future research targeted on those features of FOXP1 syndrome that most impair quality of life of patients and their families. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - March 21, 2024 Category: Genetics & Stem Cells Authors: Koene, S., Ropers, F. G., Wieland, J., Rybak, T., Wildschut, F., Berghuis, D., Morgan, A., Trelles, M. P., Scheepe, J. R., Bökenkamp, R., Peeters-Scholte, C. M. P. C. D., Braden, R., Santen, G. W. E. Tags: Phenotypes Source Type: research
