scholarly journals Correction: Møller, P.; et al. Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift. Cancers 2019, 11, 132

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 410
Author(s):  
Møller ◽  
Dominguez-Valentin ◽  
Rødland ◽  
Hovig
Keyword(s):  
Genetic Drift ◽  
De Novo ◽  
De Novo Mutations

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. [...]

scholarly journals Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 132 ◽  
Author(s):  
Pål Møller ◽  
Mev Dominguez-Valentin ◽  
Einar Rødland ◽  
Eivind Hovig
Keyword(s):  
Breast Cancer ◽  
Confidence Interval ◽  
Genetic Drift ◽  
De Novo ◽  
Prophylactic Mastectomy ◽  
Cumulative Risk ◽  
Surrogate Marker ◽  
De Novo Mutations ◽  
High Prevalence ◽  
Low Incidence

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10–30%), compared to 35% (95% confidence interval 22–48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32–39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
MS Oud ◽  
RM Smits ◽  
HE Smith ◽  
FK Mastrorosa ◽  
GS Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
Joris Veltman ◽  
Manon Oud ◽  
Roos Smits ◽  
Hannah Smith ◽  
Francesco Mastrorosa ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

Abstract De novo mutations (DNMs) are known to play a prominent role in many sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. We performed a trio-based exome-sequencing study in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

scholarly journals A de novo paradigm for male infertility

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
M. S. Oud ◽  
R. M. Smits ◽  
H. E. Smith ◽  
F. K. Mastrorosa ◽  
G. S. Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment ◽  
Infertile Patients

AbstractDe novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Eine Therapie mit Everolimus und reduziertem Ciclosporin kann das Krebsrisiko von Nierentransplantierten verringern* (Sponsor: Novartis Pharma GmbH, Nürnberg)

2017 ◽  
Vol 05 (01) ◽  
pp. 22-22
Keyword(s):  
New Zealand ◽  
De Novo

ZusammenfassungDie Verknüpfung der A2309-Studie mit dem Australia and New Zealand Dialysis and Transplant (ANZDATA) Register erlaubte ein Follow up von 7 Jahren. Die Autoren bezeichnen diese Analyse als die bisher überzeugendste Evidenz, dass eine Immunsuppression mit de novo Everolimus und reduziertem Ciclosporin langfristig mit einer geringeren Krebsinzidenz nach Nierentransplantation assoziiert ist als die Standardtherapie.

BioMime – A Sirolimus-eluting Coronary Stent System for the Treatment of Patients with De Novo Coronary Lesions – meriT-1 Report

2011 ◽  
Vol 6 (1) ◽  
pp. 39
Author(s):  
Keyword(s):  
Stent Thrombosis ◽  
Time Course ◽  
De Novo ◽  
Drug Eluting Stent ◽  
Cobalt Chromium ◽  
Cardiac Events ◽  
End Points ◽  
Safety And Efficacy ◽  
Binary Restenosis

Background:Since the first reported use of percutaneous transluminal coronary angioplasty, advances in the interventional cardiology arena have been fast paced. Developers and clinicians are adapting from the learning curve awarded by the time-course of drug-eluting stent (DES) evolution. BioMime™ sirolimus-eluting stent (SES) is a step towards biomimicry. The stent is built on a strut of ultra-low thickness (65μm), a cobalt–chromium platform using an intelligent hybrid of closed and open cells allowing for morphology-mediated expansion. It employs a well-known antiproliferative – sirolimus – that elutes from a known biodegradable copolymer formulation within 30 days. The resultant stent demonstrates almost 100% endothelialisation at 30 days in preclinical models.Methods:The meriT-1 was a prospective, single-arm, single-centre trial to evaluate the safety and efficacy of BioMime SES in 30 patients with a single de novo lesion in native coronary arteries. The primary safety and efficacy end-points were major adverse cardiac events (MACE) at 30 days and in-stent late lumen loss at eight months, as measured using quantitative coronary angiographic (QCA) method. Secondary safety and efficacy end-points included MACE at one and two years and angiographic binary restenosis at eight-month angiographic follow-up. Other end-points included the occurrence of stent thrombosis at acute, subacute, late and very late periods and the percentage of diameter stenosis by QCA.Results:No MACE were observed and the median in-stent late luminal loss in 20 (67%) subjects studied by QCA was 0.15mm, with 0% binary restenosis at eight-month follow-up. No stent thrombosis was observed up to one-year follow-up.Conclusions:In comparison to currently available DES, BioMime SES appears to have a considerable scientific basis for prevention of neointimal proliferation, restenosis and associated clinical events.

Is 3 years adequate for tracking completely occluded coiled aneurysms?

2020 ◽  
Vol 133 (3) ◽  
pp. 758-764
Author(s):  
Eung Koo Yeon ◽  
Young Dae Cho ◽  
Dong Hyun Yoo ◽  
Su Hwan Lee ◽  
Hyun-Seung Kang ◽  
...  
Keyword(s):  
De Novo ◽  
Careful Monitoring ◽  
Surveillance Period ◽  
Radiological Data ◽  
De Novo Aneurysm ◽  
Low Probability ◽  
Almost All ◽  
Annual Risk

OBJECTIVEThe authors conducted a study to ascertain the long-term durability of coiled aneurysms completely occluded at 36 months’ follow-up given the potential for delayed recanalization.METHODSIn this retrospective review, the authors examined 299 patients with 339 aneurysms, all shown to be completely occluded at 36 months on follow-up images obtained between 2011 and 2013. Medical records and radiological data acquired during the extended monitoring period (mean 74.3 ± 22.5 months) were retrieved, and the authors analyzed the incidence of (including mean annual risk) and risk factors for delayed recanalization.RESULTSA total of 5 coiled aneurysms (1.5%) occluded completely at 36 months showed recanalization (0.46% per aneurysm-year) during the long-term surveillance period (1081.9 aneurysm-years), 2 surfacing within 60 months and 3 developing thereafter. Four showed minor recanalization, with only one instance of major recanalization. The latter involved the posterior communicating artery as an apparent de novo lesion, arising at the neck of a firmly coiled sac, and was unrelated to coil compaction or growth. Additional embolization was undertaken. In a multivariate analysis, a second embolization for a recurrent aneurysm (HR = 22.088, p = 0.003) independently correlated with delayed recanalization.CONCLUSIONSAlmost all coiled aneurysms (98.5%) showing complete occlusion at 36 months postembolization proved to be stable during extended observation. However, recurrent aneurysms were predisposed to delayed recanalization. Given the low probability yet seriousness of delayed recanalization and the possibility of de novo aneurysm formation, careful monitoring may be still considered in this setting but at less frequent intervals beyond 36 months.

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