Recurrent small deletions in KCNQ1OT1: a challenge for pathogenicity prediction
In the articles linked to this commentary and also published by the Journal of Medical Genetics, two groups independently report on the same small deletion in 11p15.5 which affects the imprinting centre 2 (IC2).1 2 With another recently published patient,3 now three families with the same rare molecular deletion of 132 bp in the IC2 are documented. In two families, the growth retardation phenotype segregates with the paternal origin of the affected allele and fits with the imprinting status of the region, but the description of a healthy carrier of the 132 bp deletion in the paternal IC2 copy by Stoltze2 shows that this co...
Source: Journal of Medical Genetics - January 24, 2023 Category: Genetics & Stem Cells Authors: Eggermann, T. Tags: Epigenetics Source Type: research
Maternal versus paternal inheritance of a 132 bp 11p15.5 microdeletion affecting KCNQ1OT1 and associated phenotypes
In this brief communication, we address the possible associations of a 132 bp deletion within the antisense gene KCNQ1OT1 on 11p15.5 to growth abnormalities. We question its recently suggested connection of paternal inheritance with Silver-Russell syndrome (SRS; OMIM #180860) and demonstrate maternal inheritance of the same variant in a 16-year-old girl with a tumour of the left leg. She also had mild isolated hemihypertrophy, suggesting a possible link to Beckwith-Wiedemann syndrome (BWS; OMIM #130650). Our findings underscore the complexity of 11p15.5 structural variations and the diffidence required when assessing their...
Source: Journal of Medical Genetics - January 24, 2023 Category: Genetics & Stem Cells Authors: Stoltze, U. K., Hansen, T. V. O., Brok, J. S., Gronskov, K., Tumer, A. Z., Ahlborn, L. B., Schmiegelow, K., Wadt, K. A. W. Tags: Open access Epigenetics Source Type: research
Familial risk of epithelial ovarian cancer after accounting for gynaecological surgery: a population-based study
Conclusion
Familial risk of epithelial ovarian cancer extends to TDRs, especially for high-grade serous and mucinous histotypes. Distant relatives share genes but minimal environment, highlighting the importance of germline inherited genetics in ovarian cancer aetiology. Increased ovarian cancer risk in distant relatives has implications for counselling and recommendations for prophylactic surgeries that, from our data, appear only to reach FDRs. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - January 24, 2023 Category: Genetics & Stem Cells Authors: Barnard, M. E., Meeks, H., Jarboe, E. A., Albro, J., Camp, N. J., Doherty, J. A. Tags: Open access Cancer genetics Source Type: research
Contribution of large genomic rearrangements in PALB2 to familial breast cancer: implications for genetic testing
Conclusions
Our data show that a clinically important proportion of PALB2 pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion of PALB2 LGRs in routine clinical genetic testing. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - January 24, 2023 Category: Genetics & Stem Cells Authors: Li, N., Zethoven, M., McInerny, S., Healey, E., DeSilva, D., Devereux, L., Scott, R. J., James, P. A., Campbell, I. G. Tags: Cancer genetics Source Type: research
UK recommendations for SDHA germline genetic testing and surveillance in clinical practice
SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive prot...
Source: Journal of Medical Genetics - January 24, 2023 Category: Genetics & Stem Cells Authors: Hanson, H., Durkie, M., Lalloo, F., Izatt, L., McVeigh, T. P., Cook, J. A., Brewer, C., Drummond, J., Butler, S., Cranston, T., Casey, R., Tan, T., Morganstein, D., Eccles, D. M., Tischkowitz, M., Turnbull, C., Woodward, E. R., Maher, E. R., on behalf of Tags: Open access Position statement Source Type: research
Detection of copy number variants associated with late-onset conditions in ~16 200 pregnancies: parameters for disclosure and pregnancy outcome
Conclusions
Our suggested DDT will help clinicians to quantitatively weigh the variables associated with CNVs of this type and arrive at a well thought out clinical decision regarding disclosure. Although the prevalence of late-onset conditions as a major finding in the prenatal setup is low, it is expected to rise with the increasing use of non-invasive CMA testing and whole exome and genome sequencing. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Daum, H., Segel, R., Meiner, V., Goldberg, Y., Zeligson, S., Weiss, O., Stern, S., Frumkin, A., Zenvirt, S., Ganz, G., Shkedi-Rafid, S. Tags: Copy-number variation Source Type: research
Impaired social cognition and fine dexterity in patients with Cowden syndrome associated with germline PTEN variants
Conclusion
Altered social cognition and impaired fine dexterity are frequently associated with CS. Further studies are needed to confirm these results and to determine whether dexterity impairment is due to the effect of germline PTEN variants in the cerebellum. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Desjardins, C., Caux, F., Degos, B., Benzohra, D., De Liege, A., Bohelay, G., Longy, M., Bereaux, C., Garcin, B. Tags: Cognitive and behavioural genetics Source Type: research
Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts
Conclusion
WILD syndrome is a previously unrecognised, underdiagnosed generalised PL syndrome. Based on this case series, we redefine WILD as ‘Warts, Immunodeficiency, andLymphatic Dysplasia’ and suggest specific diagnostic criteria. The essential criterion is congenital multisegmental PL in a ‘mosaic’ distribution. The major diagnostic features are recurrent warts, cutaneous lymphovascular malformations, systemic involvement (lymphatic dysplasia), genital swelling and CD4 lymphopaenia with normal monocyte counts. The absence of family history suggests a sporadic condition, and the random distributi...
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Mansour, S., Josephs, K. S., Ostergaard, P., Gordon, K., Van Zanten, M., Pearce, J., Jeffery, S., Keeley, V., Riches, K., Kreuter, A., Wieland, U., Hägerling, R., Ratnam, L., Sackey, E., Grigoriadis, D., Ho, B., Smith, F., Rauter, E., Mortimer, P. Tags: Open access Phenotypes Source Type: research
Pharmacogenomic testing and prescribing patterns for patients with cancer in a large national precision medicine cohort
Population databases could help patients with cancer and providers better understand current pharmacogenomic prescribing and testing practices. This retrospective observational study analysed patients with cancer, drugs with pharmacogenomic evidence and related genetic testing in the National Institutes of Health All of Us database. Most patients with cancer (19 633 (88.3%) vs 2590 (11.7%)) received ≥1 drug and 36 (0.2%) received genetic testing, with a significant association between receiving ≥1 drug and age group (p<0.001), but not sex (p=0.612), race (p=0.232) or ethnicity (p=0.971). Drugs with pharmacogenomic...
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Ronquillo, J. G., Lester, W. T. Tags: Therapeutics Source Type: research
Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome
Conclusions
We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. Patients harbouring pathogenic FBN1 variants with these genetic risk factors should be monitored carefully for scoliosis progression. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Taniguchi, Y., Takeda, N., Inuzuka, R., Matsubayashi, Y., Kato, S., Doi, T., Yagi, H., Yamauchi, H., Ando, M., Oshima, Y., Tanaka, S. Tags: Open access Genotype-phenotype correlations Source Type: research
Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study
Conclusion
Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Björkman, K., Vissing, J., Ostergaard, E., Bindoff, L. A., de Coo, I. F. M., Engvall, M., Hikmat, O., Isohanni, P., Kollberg, G., Lindberg, C., Majamaa, K., Naess, K., Uusimaa, J., Tulinius, M., Darin, N. Tags: Open access Genotype-phenotype correlations Source Type: research
Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis
Conclusion
Pathogenic heterozygous ANGPT2 missense variants were recently shown to cause autosomal dominant primary lymphoedema. ANGPT2 is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive ANGPT...
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Smeland, M. F., Brouillard, P., Prescott, T., Boon, L. M., Hvingel, B., Nordbakken, C. V., Nystad, M., Holla, O. L., Vikkula, M. Tags: Open access Developmental defects Source Type: research
Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex
Conclusion
Our study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Falb, R. J., Müller, A. J., Klein, W., Grimmel, M., Grasshoff, U., Spranger, S., Stöbe, P., Gauck, D., Kuechler, A., Dikow, N., Schwaibold, E. M. C., Schmidt, C., Averdunk, L., Buchert, R., Heinrich, T., Prodan, N., Park, J., Kehrer, M., S Tags: Open access Novel disease loci Source Type: research
Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC)
Conclusion
Annual CERMRI in HLRCC is cost-effective across age groups modelled. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Thompson, A. J., Alwan, Y. M., Ramani, V. A. C., Evans, D. G., Maher, E. R., Woodward, E. R. Tags: Cancer genetics Source Type: research
Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants
Conclusion
In consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria. (Source: Journal of Medical Genetics)
Source: Journal of Medical Genetics - December 23, 2022 Category: Genetics & Stem Cells Authors: Lerner, B. A., Xicola, R. M., Rodriguez, N. J., Karam, R., Llor, X. Tags: Cancer genetics Source Type: research
