Surprising genetic and pathological findings in a patient with giant bilateral periadrenal tumours: PEComas and mutations of PTCH1 in Gorlin-Goltz syndrome
Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient’s blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gen...
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Igaz, P., Toth, G., Nagy, P., Dezso, K., Turai, P. I., Medvecz, M., Wikonkal, N., Huszty, G., Piros, L., Toth, E., Bozsik, A., Liko, I., Patocs, A., Butz, H. Tags: Cancer genetics Source Type: research
Catastrophic chemotherapy toxicity leading to diagnosis of Fanconi anaemia due to FANCD1/BRCA2 during adulthood: description of an emerging phenotype
This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although...
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Ip, E., McNeil, C., Grimison, P., Scheinberg, T., Tudini, E., Ho, G., Scott, R. J., Brown, C., Sandroussi, C., Guitera, P., Spurdle, A. B., Goodwin, A. Tags: Cancer genetics Source Type: research
Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality
Conclusion
Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Machado, R. D., Welch, C. L., Haimel, M., Bleda, M., Colglazier, E., Coulson, J. D., Debeljak, M., Ekstein, J., Fineman, J. R., Golden, W. C., Griffin, E. L., Hadinnapola, C., Harris, M. A., Hirsch, Y., Hoover-Fong, J. E., Nogee, L., Romer, L. H., Vesel, Tags: Open access Novel disease loci Source Type: research
New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements
Conclusion
Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Romanelli Tavares, V. L., Guimaraes-Ramos, S. L., Zhou, Y., Masotti, C., Ezquina, S., Moreira, D. d. P., Buermans, H., Freitas, R. S., Den Dunnen, J. T., Twigg, S. R. F., Passos-Bueno, M. R. Tags: Open access Novel disease loci Source Type: research
SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum
Conclusion
Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Serpieri, V., DAbrusco, F., Dempsey, J. C., Cheng, Y.-H. H., Arrigoni, F., Baker, J., Battini, R., Bertini, E. S., Borgatti, R., Christman, A. K., Curry, C., D'Arrigo, S., Fluss, J., Freilinger, M., Gana, S., Ishak, G. E., Leuzzi, V., Loucks, H., Manti, F Tags: Open access Neurogenetics Source Type: research
Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes
Conclusion
Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Laugwitz, L., Seibt, A., Herebian, D., Peralta, S., Kienzle, I., Buchert, R., Falb, R., Gauck, D., Müller, A., Grimmel, M., Beck-Woedel, S., Kern, J., Daliri, K., Katibeh, P., Danhauser, K., Leiz, S., Alesi, V., Baertling, F., Vasco, G., Steinfeld Tags: Neurogenetics Source Type: research
Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14)
Conclusion
This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Minatogawa, M., Unzaki, A., Morisaki, H., Syx, D., Sonoda, T., Janecke, A. R., Slavotinek, A., Voermans, N. C., Lacassie, Y., Mendoza-Londono, R., Wierenga, K. J., Jayakar, P., Gahl, W. A., Tifft, C. J., Figuera, L. E., Hilhorst-Hofstee, Y., Maugeri, A., Tags: Open access Phenotypes Source Type: research
Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy--risk of arrhythmias and heart failure
Conclusion
In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Christensen, A. H., Platonov, P. G., Jensen, H. K., Chivulescu, M., Svensson, A., Dahlberg, P., Madsen, T., Frederiksen, T. C., Heliö, T., Lie, O. H., Haugaa, K. H., Hastrup Svendsen, J., Bundgaard, H. Tags: Genotype-phenotype correlations Source Type: research
Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest
Conclusion
These findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Zheng, W., Sha, Q.-Q., Hu, H., Meng, F., Zhou, Q., Chen, X., Zhang, S., Gu, Y., Yan, X., Zhao, L., Zong, Y., Hu, L., Gong, F., Lu, G., Fan, H.-Y., Lin, G. Tags: Genotype-phenotype correlations Source Type: research
Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population
Conclusions
Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Chen, Y.-P., Yu, S.-H., Wei, Q.-Q., Cao, B., Gu, X.-J., Chen, X.-P., Song, W., Zhao, B., Wu, Y., Sun, M.-M., Liu, F.-F., Hou, Y.-B., Ou, R.-W., Zhang, L.-Y., Liu, K.-C., Lin, J.-Y., Xu, X.-R., Li, C.-Y., Yang, J., Jiang, Z., Liu, J., Cheng, Y.-F., Xiao, Y Tags: Open access Genotype-phenotype correlations Source Type: research
The role of single-cell genomics in human genetics
Single-cell sequencing is a powerful approach that can detect genetic alterations and their phenotypic consequences in the context of human development, with cellular resolution. Humans start out as single-cell zygotes and undergo fission and differentiation to develop into multicellular organisms. Before fertilisation and during development, the cellular genome acquires hundreds of mutations that propagate down the cell lineage. Whether germline or somatic in nature, some of these mutations may have significant genotypic impact and lead to diseased cellular phenotypes, either systemically or confined to a tissue. Single-c...
Source: Journal of Medical Genetics - August 19, 2022 Category: Genetics & Stem Cells Authors: Sreenivasan, V. K. A., Balachandran, S., Spielmann, M. Tags: Open access Review Source Type: research
A step forward, but still inadequate: Australian health professionals views on the genetics and life insurance moratorium
Conclusion
While the current Australian moratorium is considered a step forward, most HPs believe it falls short of an adequate long-term regulatory solution to GD in life insurance. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - July 21, 2022 Category: Genetics & Stem Cells Authors: Tiller, J. M., Keogh, L. A., McInerney-Leo, A. M., Belcher, A., Barlow-Stewart, K., Boughtwood, T., Gleeson, P., Dowling, G., Prince, A., Bombard, Y., Joly, Y., Delatycki, M., Winship, I. M., Otlowski, M., Lacaze, P. Tags: Ethics and policy Source Type: research
Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review
Conclusion
Common phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - July 21, 2022 Category: Genetics & Stem Cells Authors: Durkin, A., DeVile, C., Arundel, P., Bull, M., Walsh, J., Bishop, N. J., Hupin, E., Parekh, S., Nadarajah, R., Offiah, A. C., Calder, A., Brock, J., Baker, D., Balasubramanian, M. Tags: Phenotypes Source Type: research
Myasthenia gravis genome-wide association study implicates AGRN as a risk locus
Discussion
Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - July 21, 2022 Category: Genetics & Stem Cells Authors: Topaloudi, A., Zagoriti, Z., Flint, A. C., Martinez, M. B., Yang, Z., Tsetsos, F., Christou, Y.-P., Lagoumintzis, G., Yannaki, E., Zamba-Papanicolaou, E., Tzartos, J., Tsekmekidou, X., Kotsa, K., Maltezos, E., Papanas, N., Papazoglou, D., Passadakis, P., Tags: Genome-wide studies Source Type: research
Oncology clinic-based germline genetic testing for exocrine pancreatic cancer enables timely return of results and unveils low uptake of cascade testing
Conclusion
A point-of-care GT model is feasible and expedites access to GT for patients with PC. Strategies to increase the uptake of cascade testing are needed to maximise the clinical impact of an oncology clinic-based GT model. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - July 21, 2022 Category: Genetics & Stem Cells Authors: Wang, Y., Golesworthy, B., Cuggia, A., Domecq, C., Chaudhury, P., Barkun, J., Metrakos, P., Asselah, J., Bouganim, N., Gao, Z.-H., Chong, G., Foulkes, W. D., Zogopoulos, G. Tags: Cancer genetics Source Type: research
