64 results on '"Skytte AB"'
Search Results
2. Tofacitinib Does Not Impair Sperm Quality in Men With Ulcerative Colitis.
- Author
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Grosen A, Bellaguarda E, Liljeqvist-Soltic I, Skytte AB, Hanauer SB, and Kelsen J
- Published
- 2024
- Full Text
- View/download PDF
3. Recent decline in sperm motility among donor candidates at a sperm bank in Denmark.
- Author
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Lassen E, Pacey A, Skytte AB, and Montgomerie R
- Subjects
- Humans, Male, Denmark, Adult, Middle Aged, Sperm Count, Young Adult, Adolescent, Spermatozoa physiology, Sperm Motility, Semen Analysis, Tissue Donors, Sperm Banks
- Abstract
Study Question: Has there been variation in semen quality among men applying to be sperm donors (i.e. donor candidates) in Denmark in recent years (2017-2022)?, Summary Answer: The motile sperm concentration and total motile sperm count (TMSC) in ejaculates-both measures of sperm quality-declined by as much as 22% from 2019 to 2022., What Is Known Already: Questions remain about whether human semen quality has declined in recent years. Whilst some studies provide evidence for a decline in human semen quality, these findings have been disputed owing to potential biases in the populations studied or in the methods used to measure semen quality. Resolution of this issue has important implications for human fertility, as well as for those involved in the recruitment of sperm donors for use in medically assisted reproduction., Study Design, Size, Duration: We obtained data on the semen quality of ejaculates previously collected from 2017 to 2022 at sperm bank locations in four cities in Denmark: Aarhus, Aalborg, Copenhagen, and Odense. Our study focuses on the single semen samples provided by 6758 donor candidates aged between 18 and 45 years old to determine whether their sperm quality met a minimum criterion for them to be accepted as sperm donors., Participants/materials, Setting, Methods: All ejaculates were analyzed within 1 hour of production. Semen volume (ml) was estimated by weight and both the concentration (106/ml) of sperm as well as the concentration of motile sperm (World Health Organization grades a and b) were measured using the same protocols and computer-assisted semen analysis system across all years at each site. Statistical analyses of the semen variables were controlled for age and donation site, as well as the average monthly high temperature when the ejaculate was produced., Main Results and the Role of Chance: From 2017 to 2019, semen volume, sperm concentration, and total sperm count in the ejaculates of donor candidates increased by 2-12%. Then, from 2019 to 2022, sperm concentration and total sperm count changed by 0.1-5% from year to year, but none of those changes were statistically significant. In contrast, both motile sperm concentration and TMSC declined significantly, by 16% and 22%, respectively, between 2019 and 2022. Thus, the concentration of motile sperm in donor candidates declined from 18.4 [95% CL: 17.0, 20.0] million/ml in 2019 to 15.5 [14.4, 16.7] million/ml in 2022, and TMSC declined from 61.4 [55.8, 67.5] million per ejaculate in 2019 to 48.1 [44.1, 52.4] million in 2022., Limitations, Reasons for Caution: We cannot determine from the available data the causes of the decline in semen quality of donor candidates from 2019 to 2022. However, as this period coincides with lockdowns and changes in work patterns during the coronavirus disease 2019 pandemic, it is possible that changes in motile sperm concentration and TMSC were the result of changes in the lifestyles of the men whose semen was analyzed., Wider Implications of the Findings: Men providing initial semen samples at sperm banks, when applying to be sperm donors, are a useful population in which to monitor changes in human semen quality over time. Our results have implications for human fertility and the recruitment of sperm donors for medically assisted reproduction, where motile sperm concentration is an essential selection criterion because it influences fertility. We suggest that gathering health and lifestyle data on donor candidates at sperm banks might help to identify causal factors for the decline of sperm quality that could be addressed and intervention, if desired, could be personalized for each accepted donor., Study Funding/competing Interest(s): No external funding was obtained for this study. E.L. and A.-B.S. are employees of Cryos International. AP reports paid consultancy for Cryos International, Cytoswim Ltd, Exceed Health, and Merck Serono in the last 2 years of this study, but all monies were paid to the University of Sheffield (former employer). AP is also an unpaid trustee of the Progress Educational Trust (Charity Number 1139856). RM declares support from Cryos International to present results of this research at ESHRE 2023. None of the authors were directly involved in the collection or physical analysis of semen samples., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
- Published
- 2024
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4. DNA mismatch and damage patterns revealed by single-molecule sequencing.
- Author
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Liu MH, Costa BM, Bianchini EC, Choi U, Bandler RC, Lassen E, Grońska-Pęski M, Schwing A, Murphy ZR, Rosenkjær D, Picciotto S, Bianchi V, Stengs L, Edwards M, Nunes NM, Loh CA, Truong TK, Brand RE, Pastinen T, Wagner JR, Skytte AB, Tabori U, Shoag JE, and Evrony GD
- Subjects
- Humans, Aging genetics, APOBEC Deaminases genetics, APOBEC Deaminases metabolism, Cytidine Deaminase metabolism, Cytidine Deaminase genetics, Cytosine metabolism, Deamination, DNA Mismatch Repair genetics, DNA Replication genetics, Genome, Mitochondrial genetics, Mutation, Neoplasms genetics, Male, Female, Base Pair Mismatch genetics, DNA Damage genetics, DNA, Single-Stranded genetics, Sequence Analysis, DNA methods, Sequence Analysis, DNA standards, Single Molecule Imaging methods
- Abstract
Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases
1,2 . Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4 . However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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5. Four decades of sperm donation: motivation and attitudes among donors.
- Author
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Lassen E, Kesmodel US, Bay B, and Skytte AB
- Subjects
- Humans, Male, Semen, Tissue Donors, Attitude, Spermatozoa, Surveys and Questionnaires, Motivation, Tissue and Organ Procurement
- Abstract
Competing Interests: Declaration of interests E.L. is an employee of Cryos International Sperm and Egg Bank. U.S.K. reports grants from Gedeon Richter, Merck, and IBSA; honoraria from Tillotts Pharma and Merck; travel support from Merck outside the submitted work. U.S.K. is also an employee of Cryos International Sperm and Egg Bank. K B.B. is a former employee of Cryos International Sperm and Egg Bank. A.B.S. is an employee of Cryos International Sperm and Egg Bank.
- Published
- 2024
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6. The impact of acute SARS-CoV-2 on testicular function including insulin-like factor 3 (INSL3) in men with mild COVID-19: A longitudinal study.
- Author
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Lauritsen MP, Kristensen TL, Hansen CB, Schneider UV, Talbot AL, Skytte AB, Petersen JH, Johannsen TH, Zedeler A, Albrethsen J, Juul A, Priskorn L, Jørgensen N, Westh H, Freiesleben NC, and Nielsen HS
- Subjects
- Adult, Humans, Male, Longitudinal Studies, Luteinizing Hormone, RNA, Viral, SARS-CoV-2, Semen, Testosterone, COVID-19, Insulins
- Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect the male reproductive system as it uses angiotensin-converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long-term effects of mild coronavirus disease 2019 (COVID-19) on testicular function, and insulin-like factor 3 (INSL3) levels have not previously been assessed during acute SARS-CoV-2 infection., Objectives: The aim of the study was to assess the impact of acute SARS-CoV-2 infection on testicular function including INSL3 and the presence of SARS-CoV-2 RNA in semen in non-hospitalised men with mild COVID-19., Materials and Methods: This longitudinal study included 36 non-hospitalised SARS-CoV-2-positive men (median age 29 years). Inclusion was within seven days following a positive SARS-CoV-2 reverse-transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS-CoV-2 RNA in oropharyngeal and semen samples were assessed during acute SARS-CoV-2 infection (baseline) and at three- and six-month follow-up. Wilcoxon matched-pair signed-rank (two samples) test was used to assess time-related alterations in reproductive hormone levels and semen parameters., Results: Lower plasma testosterone (T) (total and calculated free (c-fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS-CoV-2 infection (baseline) compared to three- and six-month follow-up. Consequently, ratios of c-fT/LH were lower at baseline compared to three- and six-month follow-up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three-month follow-up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six-month follow-up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS-CoV-2-related fever episodes or not. No SARS-CoV-2 RNA was detected in semen at any time point., Discussion and Conclusion: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS-CoV-2 infection. The risk of transmission of SARS-CoV-2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS-CoV-2 cannot be excluded., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)
- Published
- 2024
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7. Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.
- Author
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Block I, Mateu-Regué À, Do TTN, Miceikaite I, Sdogati D, Larsen MJ, Hao Q, Nielsen HR, Boonen SE, Skytte AB, Jensen UB, Høffding LK, De Nicolo A, Viel A, Tudini E, Parsons MT, Hansen TVO, Rossing M, Kruse TA, Spurdle AB, and Thomassen M
- Subjects
- Humans, Male, BRCA1 Protein genetics, Exons genetics, Mitomycin, Phenotype, Breast Neoplasms, Fanconi Anemia genetics
- Abstract
Background: Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype., Methods: We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells., Results: Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability., Conclusions: This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants., (© 2024. The Author(s).)
- Published
- 2024
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8. Single duplex DNA sequencing with CODEC detects mutations with high sensitivity.
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Bae JH, Liu R, Roberts E, Nguyen E, Tabrizi S, Rhoades J, Blewett T, Xiong K, Gydush G, Shea D, An Z, Patel S, Cheng J, Sridhar S, Liu MH, Lassen E, Skytte AB, Grońska-Pęski M, Shoag JE, Evrony GD, Parsons HA, Mayer EL, Makrigiorgos GM, Golub TR, and Adalsteinsson VA
- Subjects
- Male, Humans, Adult, Mutation genetics, Sequence Analysis, DNA, DNA, High-Throughput Nucleotide Sequencing, Semen, Neoplasms genetics, Neoplasms diagnosis
- Abstract
Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next-generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules ('single duplexes') to discern the true mutations on both strands. Here we present Concatenating Original Duplex for Error Correction (CODEC), which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than duplex sequencing. CODEC revealed mutation frequencies of 2.72 × 10
-8 in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide, clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability with 10-fold greater sensitivity and mutational signatures, and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations, which are commonly obscured by NGS errors., (© 2023. The Author(s).)- Published
- 2023
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9. An analysis of the outcome of 11 712 men applying to be sperm donors in Denmark and the USA.
- Author
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Pacey AA, Pennings G, Mocanu E, Rothmar J, Pinborg A, Adrian SW, Burke C, and Skytte AB
- Subjects
- Humans, Male, Tissue Donors, Spermatozoa, Denmark, Disclosure, Semen
- Abstract
Study Question: Is the outcome of donor recruitment influenced by the country in which recruitment took place or the initial identity (ID)-release choice of applicants?, Summary Answer: More applicants are accepted as donors in Denmark than in the USA and those who choose ID release are more frequently accepted than those who do not., What Is Known Already: The successful recruitment of sperm donors is essential to provide a range of medically assisted reproduction (MAR) procedures, which rely upon donor sperm. However, while much has been written about the medical screening and assessment of sperm donors from a safety perspective, relatively little has been written about the process of recruiting donors and how it works in practice. There are differences in demographic characteristics between donors who choose to allow their identity to be released to their donor offspring (ID release) compared to those who do not (non-ID release). These characteristics may also influence the likelihood of them being recruited., Study Design, Size, Duration: A total of 11 712 men applied to be sperm donors at a sperm bank in Denmark and the USA during 2018 and 2019., Participants/materials, Setting, Methods: Anonymized records of all donor applicants were examined to assess the number passing through (or lost) at each stage of the recruitment process. Statistical analysis was carried out to examine differences between location (Denmark or USA) and/or donor type (ID release versus non-ID release)., Main Results and the Role of Chance: Few applicants (3.79%) were accepted as donors and had samples frozen and released for use; this was higher in Denmark (6.53%) than in the USA (1.03%) (χ2 = 243.2; 1 degree of freedom (df); z = 15.60; P < 0.0001) and was higher in donors who opted at the outset to be ID release (4.70%) compared to those who did not (3.15%) (χ2 = 18.51; 1 df; z = 4.303; P < 0.0001). Most candidate donors were lost during recruitment because they: withdrew, failed to respond, did not attend an appointment, or did not return a questionnaire (54.91%); reported a disqualifying health issue or failed a screening test (17.41%); did not meet the eligibility criteria at the outset (11.71%); or did not have >5 × 106 motile sperm/ml in their post-thaw samples (11.20%). At each stage, there were statistically significant differences between countries and the donor's initial ID choice. During recruitment, some donors decided to change ID type. There were no country differences in the frequency in which this occurred (χ2 = 0.2852; 1 df; z = 0.5340; P = 0.5933), but it was more common for donors to change from non-ID release to ID release (27.19%) than the other way around (11.45%) (χ2 = 17.75; 1 df; z = 4.213; P < 0.0001), although movements in both directions did occur in both countries., Limitations, Reasons for Caution: No information was available about the demographic characteristics of the applicants, which may also have influenced their chances of being accepted as a donor (e.g. ethnicity and age). Donor recruitment procedures may differ in other locations according to local laws or guidelines., Wider Implications of the Findings: A better understanding of when and why candidate donors are lost in the recruitment process may help develop leaner and more efficient pathways for interested donors and sperm banks. This could ultimately increase the number of donors recruited (through enhanced information, support, and reassurance during the recruitment process) or it may reduce the financial cost to the recipients of donor sperm, thus making it more affordable to those who are ineligible for state-funded treatment., Study Funding/competing Interest(s): The study received no funding from external sources. All authors are Cryos employees or members of the Cryos External Scientific Advisory Committee., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
- Published
- 2023
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10. Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing.
- Author
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Liu MH, Costa B, Choi U, Bandler RC, Lassen E, Grońska-Pęski M, Schwing A, Murphy ZR, Rosenkjær D, Picciotto S, Bianchi V, Stengs L, Edwards M, Loh CA, Truong TK, Brand RE, Pastinen T, Wagner JR, Skytte AB, Tabori U, Shoag JE, and Evrony GD
- Abstract
Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases
1-4 . Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired5 . However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging., Competing Interests: Competing Interests A provisional patent application on HiDEF-seq has been filed (NYU Grossman School of Medicine). G.D.E. owns stock in DNA sequencing companies (Illumina, Oxford Nanopore Technologies, and Pacific Biosciences).- Published
- 2023
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11. Experiences and attitudes of Danish men who were sperm donors more than 10 years ago; a qualitative interview study.
- Author
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Lou S, Bollerup S, Terkildsen MD, Adrian SW, Pacey A, Pennings G, Vogel I, and Skytte AB
- Subjects
- Humans, Male, Tissue Donors, Spermatozoa, Denmark, Semen, Attitude
- Abstract
Background: More knowledge about the long-term impact of sperm donation is essential as the donor's attitude towards donation may change over time. Personal and social developments may prompt a rethinking of previous actions and decisions, or even regret. Thus, the aim of this study was to explore the experiences and attitudes of men who were sperm donors more than 10 years ago., Methods: From May to September 2021, semi-structured, qualitative interviews were conducted with 23 former donors (> 10 years since last donation) from Cryos International sperm bank. Two participants were non-anonymous donors and 21 were anonymous. The interviews were conducted by phone or via video (mean 24 minutes). All interviews were recorded, transcribed verbatim and rendered anonymous. Data were analyzed using thematic analysis., Results: The analysis showed that most men had been donors for monetary and altruistic purposes, and now considered sperm donation as a closed chapter that was 'unproblematic and in the past'. Most men valued anonymity and emphasized the non-relatedness between donor and donor conceived offspring. Knowledge about recipients and donor offspring was seen as 'damaging' as it could create unwanted feelings of relatedness and responsibility towards them. All men acknowledged donor conceived persons' potential interests in knowing about their genetic heritage in order to understand appearance and personal traits, but also emphasized the donors' rights to anonymity. Potential breach of anonymity was generally considered 'highly problematic' as it was expected to disturb their families and force a relationship on them., Conclusion: This study reports on former donors who might not have volunteered for research due to lack of interest or protection of privacy. The majority of men valued anonymity and clearly demarcated a line between sperm donation and fatherhood, which was enforced by not knowing about the donor offspring or recipients., Competing Interests: SL, SB, MDT and IV declare no conflict of interest. AP, GP and SWA are members of the Cryos External Scientific Advisory Committee. GP has received honorarium for this. ABS is an employee of Cryos International. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Due to anonymity issues, data material can only be made available upon reasonable request to the first author., (Copyright: © 2023 Lou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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12. Investigation of motivations for depositing sperm during the COVID-19 pandemic.
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Rosenkjær D, Skytte AB, and Kroløkke C
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- Humans, Male, Female, Motivation, Pandemics, Semen, Spermatozoa, Cryopreservation, COVID-19 epidemiology, Fertility Preservation
- Abstract
People are becoming parents later in life and with increased parental age adverse reproductive outcomes are increased. Cryopreservation of gametes enables men and women to protect, prolong and seemingly preserve their fertility. Social freezing is an increasingly popular way of cryopreservation. During the COVID-19 pandemic, the gamete bank Cryos International experienced an increased influx of men wanting to deposit their sperm. A questionnaire-based study was initiated to investigate their motivations for doing so. The results showed that the men chose to deposit mainly due to medical indications (e.g. cancer and sex change), and that the COVID-19 pandemic had no significant influence on the reason for banking their sperm. Investigations into the altruistic reasons for depositing sperm (i.e. caring for reproductive masculinity) could shed new light onto the sparsely studied topic of male reproductive journeys.
- Published
- 2023
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13. Gamete donation in the time of DNA surprises.
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Adrian SW, Ravn T, Herrmann JR, Sylvest R, Kokado M, Semba Y, Fencker M, Skytte AB, Sellmer A, Grønbaek E, Wahlberg A, and Kesmodel U
- Subjects
- Humans, DNA, Germ Cells, Oocyte Donation
- Published
- 2022
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14. Incidental finding of maternal malignancy in an unusual non-invasive prenatal test and a review of similar cases.
- Author
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Moellgaard MH, Lund ICB, Becher N, Skytte AB, Andreasen L, Srebniak MI, and Vogel I
- Abstract
We present a clinical case where a complex abnormal non-invasive prenatal test (NIPT) result in a research project revealed carcinoma of the breast in the pregnant woman. Furthermore, the NIPT result did not demonstrate the same fetal chromosomal aberration as the chorion villus sample. A literature search for similar cases was performed identifying 43 unique cases, where abnormal NIPT results were related to maternal malignancy. Malignancy is a rare but important cause of complex abnormal non-invasive prenatal test (NIPT) results and should be considered when fetal karyotype and abnormal NIPT results are discordant. Furthermore, a follow-up invasive sample is essential for correct fetal diagnosis when abnormal NIPT results are found., Competing Interests: No authors declared any conflicts of interest., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)
- Published
- 2022
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15. Effects of virtual reality erotica on ejaculate quality of sperm donors: a balanced and randomized controlled cross-over within-subjects trial.
- Author
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Rosenkjær D, Pacey A, Montgomerie R, and Skytte AB
- Subjects
- Ejaculation, Erotica, Humans, Male, Sperm Count, Sperm Motility, Spermatozoa, Semen, Virtual Reality
- Abstract
Background: Previous research has shown that the type and duration of erotic material that men have access to during masturbation can influence semen parameters. To our knowledge, the use of virtual reality (VR) headsets to present erotica has not previously been studied. We reasoned that, because VR can provide a more immersive experience to the user, semen parameters of masturbatory ejaculates may be altered., Methods: This study had a balanced and randomized controlled cross-over within-subjects design. 504 ejaculates were collected from 63 sperm donors at 4 locations in Denmark. During masturbation each donor was instructed to observe erotic material either on a touch screen monitor or using a VR headset. The order of each pair of within-subject treatments was randomized by the throw of a dice. Anonymized data were analysed with linear mixed and piecewise structural equation models., Results: Both abstinence period and VR-use influenced the total number of motile spermatozoa ejaculated. For short abstinence periods, VR-use increased the number of motile sperm in the ejaculate. However, the difference between VR and non-VR ejaculates decreased as abstinence period increased such that there was no difference at the mean abstinence period of 58 h. For longer abstinence periods, total motile sperm counts were lower, on average, when men used VR compared to those that did not., Conclusion: The use of VR headsets to view erotica had a strong positive effect on the number of motile sperm in an ejaculate when the donor's abstinence time was short (< 24 h). VR-use could improve the ejaculate quality of men who are asked to provide samples after a short period of abstinence, such as men in infertile partnerships producing samples for ART or cancer patients depositing sperm before treatment., Trial Registration: Trial retrospectively registered on 13 July 2022 at ClinicalTrials.gov. Identifier: NCT05457764., (© 2022. The Author(s).)
- Published
- 2022
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16. Normal Sperm DNA Integrity in Patients With Inflammatory Bowel Disease on Ustekinumab Maintenance Therapy.
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Grosen A, Bellaguarda E, Liljeqvist-Soltic I, Mejlby Hansen M, Skytte AB, Julsgaard M, Hanauer SB, and Kelsen J
- Subjects
- DNA, Humans, Male, Semen, Spermatozoa, Inflammatory Bowel Diseases drug therapy, Ustekinumab therapeutic use
- Published
- 2022
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17. Attitudes of sperm donors towards offspring, identity release and extended genetic screening.
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Pennings G, Mocanu E, Herrmann JR, Skytte AB, Burke C, and Pacey A
- Subjects
- Adult, Cross-Sectional Studies, Genetic Testing, Humans, Information Dissemination, Male, Motivation, Tissue Donors statistics & numerical data, Young Adult, Privacy psychology, Spermatozoa, Tissue Donors psychology
- Abstract
Research Question: What is sperm donors' attitude towards offspring, anonymity and extended genetic screening?, Design: An online questionnaire for sperm donors was administered at Cryos International in the USA and Denmark between 9 and 30 September 2020. A total of 233 donors (37 in the USA and 196 in Denmark) completed the questionnaire. This study is unique because it was performed in a setting that allows donors to choose to be either ID-release or non-ID-release donors., Results: Most donors had two motives to donate: helping childless people and/or financial compensation. ID-release donors differed significantly from non-ID-release donors in numerous aspects of the donation, including relationships with the offspring, information sharing with others and wanting information about offspring. In general, donors had a very positive attitude towards genetic testing and extended genetic screening., Conclusions: Offering the possibility for donors to be either ID-release or non-ID-release allows more donors to be recruited than if only one option were available. The multiple differences between the two donor types suggests that these are groups with profoundly different attitudes towards donation. The general attitude of donors towards genetic testing and expanded genetic screening is very positive but further studies on the attitude of candidate donors are needed., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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18. The use of expanded carrier screening of gamete donors.
- Author
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Payne MR, Skytte AB, and Harper JC
- Subjects
- Female, Humans, Male, Research, Spermatozoa, Germ Cells, Tissue Donors
- Abstract
Study Question: What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)?, Summary Answer: Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected., What Is Known Already: The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available., Study Design, Size, Duration: A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS., Participants/materials, Setting, Methods: Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data., Main Results and the Role of Chance: A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155)., Limitations, Reasons for Caution: Panel information was found on company websites and may not have been accurate., Wider Implications of the Findings: This study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients., Study Funding/competing Interest(s): No specific funding was obtained. J.C.H. is the founder of Global Women Connected, a platform to discuss women's health issues and the Embryology and PGD Academy, who deliver education in clinical embryology. She has been paid to give a lecture by Cryos in 2019. A-B.S. is an employee of Cryos International., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
- Published
- 2021
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19. New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients.
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Djursby M, Madsen MB, Frederiksen JH, Berchtold LA, Therkildsen C, Willemoe GL, Hasselby JP, Wikman F, Okkels H, Skytte AB, Nilbert M, Wadt K, Gerdes AM, and van Overeem Hansen T
- Abstract
A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC , POLE , MSH2 or PMS2 . The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo . One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC , BUB1, TP53 and RPS20 . The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20 -related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels., (Copyright © 2020 Djursby, Madsen, Frederiksen, Berchtold, Therkildsen, Willemoe, Hasselby, Wikman, Okkels, Skytte, Nilbert, Wadt, Gerdes and van Overeem Hansen.)
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- 2020
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20. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.
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Feng H, Gusev A, Pasaniuc B, Wu L, Long J, Abu-Full Z, Aittomäki K, Andrulis IL, Anton-Culver H, Antoniou AC, Arason A, Arndt V, Aronson KJ, Arun BK, Asseryanis E, Auer PL, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barrowdale D, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Białkowska K, Blanco A, Blomqvist C, Boeckx B, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brüning T, Burwinkel B, Cai Q, Caldés T, Caligo MA, Campbell I, Canisius S, Campa D, Carter BD, Carter J, Castelao JE, Chang-Claude J, Chanock SJ, Christiansen H, Chung WK, Claes KBM, Clarke CL, Couch FJ, Cox A, Cross SS, Cybulski C, Czene K, Daly MB, de la Hoya M, De Leeneer K, Dennis J, Devilee P, Diez O, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Ejlertsen B, Ellberg C, Engel C, Eriksson M, Fasching PA, Fletcher O, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gabrielson M, Ganz PA, Gapstur SM, Garber J, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Glendon G, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Haiman CA, Hall P, Hamann U, Hake C, He W, Heyworth J, Hogervorst FBL, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Huang G, Hulick PJ, Humphreys K, Imyanitov EN, Isaacs C, Jakimovska M, Jakubowska A, James P, Janavicius R, Jankowitz RC, John EM, Johnson N, Joseph V, Jung A, Karlan BY, Khusnutdinova E, Kiiski JI, Konstantopoulou I, Kristensen VN, Laitman Y, Lambrechts D, Lazaro C, Leroux D, Leslie G, Lester J, Lesueur F, Lindor N, Lindström S, Lo WY, Loud JT, Lubiński J, Makalic E, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martens JWM, Martinez ME, Matricardi L, Maurer T, Mavroudis D, McGuffog L, Meindl A, Menon U, Michailidou K, Kapoor PM, Miller A, Montagna M, Moreno F, Moserle L, Mulligan AM, Muranen TA, Nathanson KL, Neuhausen SL, Nevanlinna H, Nevelsteen I, Nielsen FC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Olsson H, Osorio A, Papp J, Park-Simon TW, Parsons MT, Pedersen IS, Peixoto A, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Plaseska-Karanfilska D, Poppe B, Pradhan N, Prajzendanc K, Presneau N, Punie K, Pylkäs K, Radice P, Rantala J, Rashid MU, Rennert G, Risch HA, Robson M, Romero A, Saloustros E, Sandler DP, Santos C, Sawyer EJ, Schmidt MK, Schmidt DF, Schmutzler RK, Schoemaker MJ, Scott RJ, Sharma P, Shu XO, Simard J, Singer CF, Skytte AB, Soucy P, Southey MC, Spinelli JJ, Spurdle AB, Stone J, Swerdlow AJ, Tapper WJ, Taylor JA, Teixeira MR, Terry MB, Teulé A, Thomassen M, Thöne K, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Torres D, Truong T, Tung N, Vachon CM, van Asperen CJ, van den Ouweland AMW, van Rensburg EJ, Vega A, Viel A, Vieiro-Balo P, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Winqvist R, Yang XR, Yannoukakos D, Ziogas A, Milne RL, Easton DF, Chenevix-Trench G, Zheng W, Kraft P, and Jiang X
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- Breast Neoplasms metabolism, Estrogens metabolism, Female, Genetic Predisposition to Disease, Genomics, Humans, Risk Assessment, Transcriptome, Vesicular Transport Proteins genetics, Breast Neoplasms genetics, Genome-Wide Association Study, Receptors, Estrogen metabolism
- Abstract
Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer., (© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.)
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- 2020
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21. Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome.
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Smerdel MP, Skytte AB, Jelsig AM, Ebbehøj E, and Stochholm K
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- Denmark, Early Detection of Cancer methods, Genetic Testing methods, Genetic Testing standards, Hamartoma Syndrome, Multiple genetics, Humans, Neoplasms, Second Primary genetics, PTEN Phosphohydrolase genetics, Early Detection of Cancer standards, Hamartoma Syndrome, Multiple diagnosis, Neoplasms, Second Primary diagnosis, Practice Guidelines as Topic
- Abstract
Introduction: Cowden syndrome is a cancer predisposition syndrome caused by pathogenic variants in PTEN. The affected patients possess an increased risk of breast, thyroid, renal, colorectal, endometrial cancers as well as malignant melanoma. Thus prophylactic surveillance and follow up is crucial for these patients., Methods: A review of the literature including existing guidelines from the years 1996 until 2017 was carried out. In total, 2078 scientific papers were identified through database searches on Cowden syndrome. Among these, 11 manuscripts were included based on scientific relevance and quality. Expert consensus was reached to define management guidelines., Results: The literature revealed a high risk of cancer in specific organs for patients diagnosed with Cowden Syndrome. Alternative management guidelines were proposed and discussed., Conclusions: Here we propose a revised set of management guidelines for patients with Cowden syndrome in Denmark to address the increased risk of various cancer types., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
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- 2020
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22. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.
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Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, Dunning AM, Redman J, Scarth J, Plaskocinska I, Luccarini C, Shah M, Pooley K, Dorling L, Lee A, Adank MA, Adlard J, Aittomäki K, Andrulis IL, Ang P, Barwell J, Bernstein JL, Bobolis K, Borg Å, Blomqvist C, Claes KBM, Concannon P, Cuggia A, Culver JO, Damiola F, de Pauw A, Diez O, Dolinsky JS, Domchek SM, Engel C, Evans DG, Fostira F, Garber J, Golmard L, Goode EL, Gruber SB, Hahnen E, Hake C, Heikkinen T, Hurley JE, Janavicius R, Kleibl Z, Kleiblova P, Konstantopoulou I, Kvist A, Laduca H, Lee ASG, Lesueur F, Maher ER, Mannermaa A, Manoukian S, McFarland R, McKinnon W, Meindl A, Metcalfe K, Mohd Taib NA, Moilanen J, Nathanson KL, Neuhausen S, Ng PS, Nguyen-Dumont T, Nielsen SM, Obermair F, Offit K, Olopade OI, Ottini L, Penkert J, Pylkäs K, Radice P, Ramus SJ, Rudaitis V, Side L, Silva-Smith R, Silvestri V, Skytte AB, Slavin T, Soukupova J, Tondini C, Trainer AH, Unzeitig G, Usha L, van Overeem Hansen T, Whitworth J, Wood M, Yip CH, Yoon SY, Yussuf A, Zogopoulos G, Goldgar D, Hopper JL, Chenevix-Trench G, Pharoah P, George SHL, Balmaña J, Houdayer C, James P, El-Haffaf Z, Ehrencrona H, Janatova M, Peterlongo P, Nevanlinna H, Schmutzler R, Teo SH, Robson M, Pal T, Couch F, Weitzel JN, Elliott A, Southey M, Winqvist R, Easton DF, Foulkes WD, Antoniou AC, and Tischkowitz M
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- Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms, Male genetics, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Internationality, Male, Middle Aged, Ovarian Neoplasms genetics, Pancreatic Neoplasms genetics, Risk, Fanconi Anemia Complementation Group N Protein genetics, Neoplasms genetics
- Abstract
Purpose: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized., Methods: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes., Results: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10
-76 ), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3 ), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3 ), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2 ). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10-3 ). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer., Conclusion: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.- Published
- 2020
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23. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness.
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Patel VL, Busch EL, Friebel TM, Cronin A, Leslie G, McGuffog L, Adlard J, Agata S, Agnarsson BA, Ahmed M, Aittomäki K, Alducci E, Andrulis IL, Arason A, Arnold N, Artioli G, Arver B, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barroso A, Barrowdale D, Belotti M, Benitez J, Bertelsen B, Blok MJ, Bodrogi I, Bonadona V, Bonanni B, Bondavalli D, Boonen SE, Borde J, Borg A, Bradbury AR, Brady A, Brewer C, Brunet J, Buecher B, Buys SS, Cabezas-Camarero S, Caldés T, Caliebe A, Caligo MA, Calvello M, Campbell IG, Carnevali I, Carrasco E, Chan TL, Chu ATW, Chung WK, Claes KBM, Collaborators GS, Collaborators E, Cook J, Cortesi L, Couch FJ, Daly MB, Damante G, Darder E, Davidson R, de la Hoya M, Puppa LD, Dennis J, Díez O, Ding YC, Ditsch N, Domchek SM, Donaldson A, Dworniczak B, Easton DF, Eccles DM, Eeles RA, Ehrencrona H, Ejlertsen B, Engel C, Evans DG, Faivre L, Faust U, Feliubadaló L, Foretova L, Fostira F, Fountzilas G, Frost D, García-Barberán V, Garre P, Gauthier-Villars M, Géczi L, Gehrig A, Gerdes AM, Gesta P, Giannini G, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gutierrez-Barrera AM, Hahnen E, Hamann U, Hauke J, Herold N, Hogervorst FBL, Honisch E, Hopper JL, Hulick PJ, Investigators K, Investigators H, Izatt L, Jager A, James P, Janavicius R, Jensen UB, Jensen TD, Johannsson OT, John EM, Joseph V, Kang E, Kast K, Kiiski JI, Kim SW, Kim Z, Ko KP, Konstantopoulou I, Kramer G, Krogh L, Kruse TA, Kwong A, Larsen M, Lasset C, Lautrup C, Lazaro C, Lee J, Lee JW, Lee MH, Lemke J, Lesueur F, Liljegren A, Lindblom A, Llovet P, Lopez-Fernández A, Lopez-Perolio I, Lorca V, Loud JT, Ma ESK, Mai PL, Manoukian S, Mari V, Martin L, Matricardi L, Mebirouk N, Medici V, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller C, Gomes DM, Montagna M, Mooij TM, Moserle L, Mouret-Fourme E, Mulligan AM, Nathanson KL, Navratilova M, Nevanlinna H, Niederacher D, Nielsen FCC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Ong KR, Osorio A, Ott CE, Palli D, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Pérez-Segura P, Peterlongo P, Petersen AH, Porteous ME, Pujana MA, Radice P, Ramser J, Rantala J, Rashid MU, Rhiem K, Rizzolo P, Robson ME, Rookus MA, Rossing CM, Ruddy KJ, Santos C, Saule C, Scarpitta R, Schmutzler RK, Schuster H, Senter L, Seynaeve CM, Shah PD, Sharma P, Shin VY, Silvestri V, Simard J, Singer CF, Skytte AB, Snape K, Solano AR, Soucy P, Southey MC, Spurdle AB, Steele L, Steinemann D, Stoppa-Lyonnet D, Stradella A, Sunde L, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tommasi S, Torres D, Toss A, Trainer AH, Tung N, van Asperen CJ, van der Baan FH, van der Kolk LE, van der Luijt RB, van Hest LP, Varesco L, Varon-Mateeva R, Viel A, Vierstraete J, Villa R, von Wachenfeldt A, Wagner P, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Wieme G, Yadav S, Yannoukakos D, Yoon SY, Zanzottera C, Zorn KK, D'Amico AV, Freedman ML, Pomerantz MM, Chenevix-Trench G, Antoniou AC, Neuhausen SL, Ottini L, Nielsen HR, and Rebbeck TR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Genetic Association Studies, Heterozygote, Humans, Male, Middle Aged, Prognosis, Risk Factors, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Genomics methods, Mutation, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 ( BRCA1/2 ) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1 . These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual., (©2019 American Association for Cancer Research.)
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- 2020
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24. Impact of genetic counseling on the uptake of contralateral prophylactic mastectomy among younger women with breast cancer.
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Terkelsen T, Rønning H, and Skytte AB
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- Adult, Breast Neoplasms genetics, Decision Making, Female, Genetic Counseling psychology, Humans, Patient Acceptance of Health Care psychology, Prospective Studies, Young Adult, BRCA1 Protein genetics, Breast Neoplasms prevention & control, Breast Neoplasms psychology, Breast Neoplasms surgery, Genetic Counseling methods, Mutation, Prophylactic Mastectomy psychology
- Abstract
Background: Preoperative genetic testing affects the surgical decision-making among women with breast cancer. To avoid breast-conserving surgery and to offer the possibility of mastectomy with immediate reconstruction in high-risk patients, genetic testing for pathogenic variants in BRCA1 or BRCA2 and a pedigree-based familial breast cancer risk assessment was offered to younger women with breast cancer in Denmark. We evaluated the impact of the risk stratification through genetic counseling on the uptake of contralateral prophylactic mastectomy (CPM). Material and methods: The prospective cohort study included all women with unilateral breast cancer before the age of 45 who participated in a genetic counseling program during their primary diagnostics in the Central Denmark Region (2013-2018). Each patient was followed from the time of the genetic test result to the end of follow-up to estimate the long-term uptake of CPM as a competing risk-adjusted cumulative incidence. We compared the uptake of CPM between the various genetic risk categories, ages of onset, and family histories in a multivariable Cox proportional hazards regression model, reporting hazard ratios (HR) with two-sided 95% confidence intervals (CIs). Results: 156 females, aged 21-44, learned their genetic test result within a median of 92 days [interquartile range (IQR): 75-114]. The maximal follow-up was 3.8 years (median 1.8; IQR: 0.49-2.5), after which 33% (95% CI: 24-42%) of the patients had undergone CPM. The uptake of CPM was inversely associated with the age of onset (HR 0.92; 95% CI: 0.86-0.98) and significantly higher among BRCA carriers (HR 2.9; 95% CI: 1.3-6.8) and patients from the high risk of breast cancer families (HR 5.6; 95% CI: 1.9-16) compared to the lower genetic risk categories. Conclusion: The risk stratification obtained through genetic counseling had a considerable impact on the surgical decision-making among younger women with breast cancer at long-term follow-up.
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- 2020
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25. Population frequencies of pathogenic alleles of BRCA1 and BRCA2: analysis of 173 Danish breast cancer pedigrees using the BOADICEA model.
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Terkelsen T, Christensen LL, Fenton DC, Jensen UB, Sunde L, Thomassen M, and Skytte AB
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- Adult, Age of Onset, Algorithms, Breast Neoplasms epidemiology, Calibration, Denmark, Female, Heterozygote, Humans, Incidence, Pedigree, United Kingdom epidemiology, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Gene Frequency, Models, Genetic
- Abstract
The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant in BRCA1 or BRCA2 based on her pedigree and the population frequencies of pathogenic alleles of BRCA1 (0.0006394) and BRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles of BRCA1 and BRCA2 for other populations but only includes preset values for the Ashkenazy Jewish and Icelandic populations. Among 173 early-onset breast cancer pedigrees in Denmark, BOADICEA discriminated well between carriers and non-carriers of pathogenic variants (area under the receiver operating characteristics curve: 0.81; 95% CI 0.74-0.86) but underestimated the frequency of carriers of pathogenic variants in BRCA1 or BRCA2 as measured by the observed-to-expected ratio (O/E 1.83; 95% CI 1.18-2.84). This reflects findings from older studies of BOADICEA in UK, German, Italian, and Chinese populations, all accounting for the different calibration for different carrier probabilities. To improve the performance of BOADICEA for non-UK populations, we developed a method to derive population frequencies of pathogenic alleles of BRCA1 and BRCA2. Compared to the UK population frequencies, we estimated the Danish population frequencies of pathogenic alleles to be higher for BRCA1 (0.0015; 95% CI 0.00064-0.0034) and lower for BRCA2 (0.00052; 95% CI 0.00018-0.0017) after adjusting for the different calibration of BOADICEA for different carrier probabilities. Incorporating additional population frequencies into BOADICEA could improve its performance for non-UK populations.
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- 2019
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26. Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice.
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Jønch AE, Douard E, Moreau C, Van Dijck A, Passeggeri M, Kooy F, Puechberty J, Campbell C, Sanlaville D, Lefroy H, Richetin S, Pain A, Geneviève D, Kini U, Le Caignec C, Lespinasse J, Skytte AB, Isidor B, Zweier C, Caberg JH, Delrue MA, Møller RS, Bojesen A, Hjalgrim H, Brasch-Andersen C, Lemyre E, Ousager LB, and Jacquemont S
- Subjects
- Case-Control Studies, Cohort Studies, Female, Heart Diseases congenital, Humans, Loss of Function Mutation, Male, Sequence Deletion, Autistic Disorder genetics, DNA Copy Number Variations, Epilepsy genetics, Heart Diseases genetics, Intellectual Disability genetics, Neurodevelopmental Disorders genetics
- Abstract
Background: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders., Methods: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant., Results: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias., Conclusions: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2019
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27. [Newborn with aplasia cutis caused by epidermolysis bullosa].
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Cramer C, Bay B, Skytte AB, Lauritzen KF, and Sommerlund M
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- Female, Humans, Infant, Newborn, Ectodermal Dysplasia etiology, Epidermolysis Bullosa complications, Epidermolysis Bullosa pathology, Epidermolysis Bullosa therapy
- Abstract
Epidermiolysis bullosa (EB) is a rare group of genetic disorders, which are characterised by bullae and erosions on skin and mucosa. This case report describes a patient, who was born at full term without any complications. Both crurae were affected by aplasia cutis. Upon birth, the newborn was wrapped in a soft blanket, and prophylactic antibiotic treatment was started along with analgesics. Large bullae were punctured with a sterile needle, and erosions were treated with non-adherent wound dressings and special bandages. Gloves and shoes were custom-made. Autosomal recessive dystrophic EB was genetically confirmed, and the child was followed regularly by an EB-team.
- Published
- 2018
28. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
- Author
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Whitworth J, Smith PS, Martin JE, West H, Luchetti A, Rodger F, Clark G, Carss K, Stephens J, Stirrups K, Penkett C, Mapeta R, Ashford S, Megy K, Shakeel H, Ahmed M, Adlard J, Barwell J, Brewer C, Casey RT, Armstrong R, Cole T, Evans DG, Fostira F, Greenhalgh L, Hanson H, Henderson A, Hoffman J, Izatt L, Kumar A, Kwong A, Lalloo F, Ong KR, Paterson J, Park SM, Chen-Shtoyerman R, Searle C, Side L, Skytte AB, Snape K, Woodward ER, Tischkowitz MD, and Maher ER
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Female, Genetic Testing methods, Germ-Line Mutation genetics, Humans, Male, Middle Aged, Phenotype, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Neoplasms, Multiple Primary genetics
- Abstract
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ
2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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29. [Dyskeratosis follicularis].
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Dorf IL, Sommerlund M, Skytte AB, and Koppelhus U
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- Databases, Factual, Humans, Retinoids therapeutic use, Darier Disease diagnosis, Darier Disease drug therapy, Darier Disease pathology, Darier Disease physiopathology
- Abstract
Dyskeratosis follicularis (or Darier's disease) is a genetic skin disease with an autosomal dominant inheritance and a prevalence of 1:100,000-1:35,000. Mutations in the gene ATP2A2 encoding the Ca2+-ATPase SERCA2 in the endoplasmatic reticulum lead to acantholysis and dyskeratosis in the epidermis, nails and mucosal membranes with resultant brown-yellow coloured, often infested skin papules and nail changes. The newly established Danish database for genodermatoses is embarking on an extensive registration of all Danish patients with Darier's disease. Hopefully, the establishment of this database will lead to better research and the formation of a patient association.
- Published
- 2018
30. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.
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Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, Leslie G, Aalfs CM, Abugattas J, Adlard J, Agata S, Aittomäki K, Andrews L, Andrulis IL, Arason A, Arnold N, Arun BK, Asseryanis E, Auerbach L, Azzollini J, Balmaña J, Barile M, Barkardottir RB, Barrowdale D, Benitez J, Berger A, Berger R, Blanco AM, Blazer KR, Blok MJ, Bonadona V, Bonanni B, Bradbury AR, Brewer C, Buecher B, Buys SS, Caldes T, Caliebe A, Caligo MA, Campbell I, Caputo SM, Chiquette J, Chung WK, Claes KBM, Collée JM, Cook J, Davidson R, de la Hoya M, De Leeneer K, de Pauw A, Delnatte C, Diez O, Ding YC, Ditsch N, Domchek SM, Dorfling CM, Velazquez C, Dworniczak B, Eason J, Easton DF, Eeles R, Ehrencrona H, Ejlertsen B, Engel C, Engert S, Evans DG, Faivre L, Feliubadaló L, Ferrer SF, Foretova L, Fowler J, Frost D, Galvão HCR, Ganz PA, Garber J, Gauthier-Villars M, Gehrig A, Gerdes AM, Gesta P, Giannini G, Giraud S, Glendon G, Godwin AK, Greene MH, Gronwald J, Gutierrez-Barrera A, Hahnen E, Hauke J, Henderson A, Hentschel J, Hogervorst FBL, Honisch E, Imyanitov EN, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jensen UB, John EM, Vijai J, Kaczmarek K, Karlan BY, Kast K, Investigators K, Kim SW, Konstantopoulou I, Korach J, Laitman Y, Lasa A, Lasset C, Lázaro C, Lee A, Lee MH, Lester J, Lesueur F, Liljegren A, Lindor NM, Longy M, Loud JT, Lu KH, Lubinski J, Machackova E, Manoukian S, Mari V, Martínez-Bouzas C, Matrai Z, Mebirouk N, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Mickys U, Miller A, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Neuhausen SL, Nevanlinna H, Ngeow J, Nguyen HP, Niederacher D, Nielsen HR, Nielsen FC, Nussbaum RL, Offit K, Öfverholm A, Ong KR, Osorio A, Papi L, Papp J, Pasini B, Pedersen IS, Peixoto A, Peruga N, Peterlongo P, Pohl E, Pradhan N, Prajzendanc K, Prieur F, Pujol P, Radice P, Ramus SJ, Rantala J, Rashid MU, Rhiem K, Robson M, Rodriguez GC, Rogers MT, Rudaitis V, Schmidt AY, Schmutzler RK, Senter L, Shah PD, Sharma P, Side LE, Simard J, Singer CF, Skytte AB, Slavin TP, Snape K, Sobol H, Southey M, Steele L, Steinemann D, Sukiennicki G, Sutter C, Szabo CI, Tan YY, Teixeira MR, Terry MB, Teulé A, Thomas A, Thull DL, Tischkowitz M, Tognazzo S, Toland AE, Topka S, Trainer AH, Tung N, van Asperen CJ, van der Hout AH, van der Kolk LE, van der Luijt RB, Van Heetvelde M, Varesco L, Varon-Mateeva R, Vega A, Villarreal-Garza C, von Wachenfeldt A, Walker L, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Yoon SY, Zanzottera C, Zidan J, Zorn KK, Hutten Selkirk CG, Hulick PJ, Chenevix-Trench G, Spurdle AB, Antoniou AC, and Nathanson KL
- Subjects
- Databases, Genetic, Family, Geography, Humans, BRCA1 Protein genetics, BRCA2 Protein genetics, Internationality, Mutation genetics
- Abstract
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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31. Childhood pneumothorax in Birt-Hogg-Dubé syndrome: A cohort study and review of the literature.
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Geilswijk M, Bendstrup E, Madsen MG, Sommerlund M, and Skytte AB
- Subjects
- Adolescent, Adult, Birt-Hogg-Dube Syndrome physiopathology, Carcinoma, Renal Cell complications, Child, Cohort Studies, Cysts complications, Female, Humans, Kidney Neoplasms complications, Male, Middle Aged, Netherlands epidemiology, Pneumothorax complications, Pneumothorax metabolism, Birt-Hogg-Dube Syndrome complications, Pneumothorax physiopathology
- Abstract
Background: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominantly inherited cancer predisposition syndrome associated with an increased risk of spontaneous pneumothorax (SP) and renal cell carcinoma in the adult population. Recent studies suggest that BHD accounts for up to 10% of all SP in adults and BHD in children with SP have been reported., Methods: To explore to what extent BHD is the cause of childhood pneumothorax, we studied a Danish BHD cohort consisting of 109 cases from 22 families. Clinical data was gathered by review of medical records. A systematic literature search concerning childhood and adolescence pneumothorax in BHD was performed and identified publications reviewed., Results: In our cohort, three of 109 BHD cases experienced childhood pneumothorax, corresponding to a prevalence of 3%. Reviewing the literature, data regarding more than 800 BHD cases were covered. Only seven previously published cases of childhood pneumothorax in BHD were identified., Conclusion: Our findings suggest that BHD is likely the cause of a larger subset of childhood pneumothoraces than hitherto recognized. Awareness of BHD as a cause of childhood pneumothorax needs to be raised to provide patients and relatives with the possibility of specialized management of SP and regular renal cancer surveillance., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2018
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32. Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark.
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Stoltze U, Skytte AB, Roed H, Hasle H, Ejlertsen B, Overeem Hansen TV, Schmiegelow K, Gerdes AM, and Wadt K
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- Adolescent, Adult, Child, Child, Preschool, Denmark, Female, Humans, Infant, Male, Middle Aged, Young Adult, Genes, p53, Germ-Line Mutation, Pedigree, Registries
- Abstract
Introduction: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration., Methods: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries., Results: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies., Conclusion: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.
- Published
- 2018
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33. A case of penta X syndrome caused by nondisjunction in maternal meiosis 1 and 2.
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Markholt S, Graakjaer J, Thim SB, Høst B, and Skytte AB
- Abstract
The prenatal abnormalities in patients with penta X syndrome appear late in pregnancy and are nonspecific. In contrast, the postnatal phenotype is well described although new findings are still revealed. Penta X syndrome is a result of successive nondisjunctions of the X chromosomes in both maternal meiotic divisions.
- Published
- 2017
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34. Birt-Hogg-Dubé syndrome: a case report and a review of the literature.
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Jensen DK, Villumsen A, Skytte AB, Madsen MG, Sommerlund M, and Bendstrup E
- Abstract
Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant inherited syndrome caused by mutations in the folliculin coding gene (FLCN). The clinical manifestations of the syndrome involve the skin, lungs, and kidneys. Because of the rarity of the syndrome, guidelines for diagnosis and management of the patients with BHDS are lacking. Objective: To present a case story and a review of the literature on BHDS in order to give an update on genetics, clinical manifestations, diagnosis, treatment, prognosis and follow-up strategies. Design: Literature review and case story. Results: A PubMed and Embase search identified 330 papers. BHDS is characterized by small benign tumors in the skin, spontaneous pneumothoraces caused by cysts in the lungs and a seven-fold increased risk of renal cancer. A case story of a young female patient presenting with pneumothorax and a family history of recurrent pneumothoraces in many relatives illustrates how the history and the diagnostic work up resulted in a diagnosis of BHDS. Conclusion: BHDS is a rare inherited disorder. In patients with spontaneous pneumothorax or cystic lung disease without any obvious explanation, BHDS should be considered. Concomitant skin manifestations, a family history of familiar pneumothorax, renal cancers and skin manifestations supports the suspicion of BHDS. Early diagnosis is important in order to subject patients to systematic screening for renal cancers. A radiological surveillance strategy for renal cancer is proposed.
- Published
- 2017
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35. Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation.
- Author
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Rossing M, Albrechtsen A, Skytte AB, Jensen UB, Ousager LB, Gerdes AM, Nielsen FC, and Hansen TV
- Subjects
- Amino Acid Sequence, Codon, Nonsense genetics, Denmark, Frameshift Mutation genetics, Genetic Predisposition to Disease, Genetic Testing, Humans, Polymorphism, Genetic genetics, Birt-Hogg-Dube Syndrome genetics, Lung Diseases genetics, Proto-Oncogene Proteins genetics, RNA Splicing genetics, Tumor Suppressor Proteins genetics
- Abstract
Pathogenic germline mutations in the folliculin (FLCN) tumor suppressor gene predispose to Birt-Hogg-Dubé (BHD) syndrome, a rare disease characterized by the development of cutaneous hamartomas (fibrofolliculomas), multiple lung cysts, spontaneous pneumothoraces and renal cell cancer. In this study, we report the identification of 13 variants and three polymorphisms in the FLCN gene in 143 Danish patients or families with suspected BHD syndrome. Functional mini-gene splicing analysis revealed that two intronic variants (c.1062+2T>G and c.1177-5_1177-3del) introduced splicing aberrations. Eleven families exhibited the c.1062+2T>G mutation. Combined single nucleotide polymorphism array-haplotype analysis showed that these families share a 3-Mb genomic fragment containing the FLCN gene, revealing that the c.1062+2T>G mutation is a Danish founder mutation. On the basis of in silico prediction and functional splicing assays, we classify the 16 identified variants in the FLCN gene as follows: nine as pathogenic, one as likely pathogenic, three as likely benign and three as polymorphisms. In conclusion, the study describes the FLCN mutation spectrum in Danish BHD patients, and contributes to a better understanding of BHD syndrome and management of BHD patients.
- Published
- 2017
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- View/download PDF
36. Diagnosis and Treatment of Blau Syndrome/Early-onset Sarcoidosis, an Autoinflammatory Granulomatous Disease, in an Infant.
- Author
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Arvesen KB, Herlin T, Larsen DA, Koppelhus U, Ramsing M, Skytte AB, and Sommerlund M
- Subjects
- Biopsy, Diagnosis, Differential, Drug Therapy, Combination, Female, Humans, Infant, Sarcoidosis, Adalimumab therapeutic use, Antirheumatic Agents therapeutic use, Arthritis diagnosis, Arthritis drug therapy, Methotrexate therapeutic use, Synovitis diagnosis, Synovitis drug therapy, Uveitis diagnosis, Uveitis drug therapy
- Published
- 2017
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37. Genetically diagnosed Birt-Hogg-Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report.
- Author
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Whitworth J, Stausbøl-Grøn B, and Skytte AB
- Subjects
- Birt-Hogg-Dube Syndrome diagnosis, Female, Humans, Middle Aged, Mutation, Birt-Hogg-Dube Syndrome genetics, Carrier Proteins genetics, Hemangioma, Cavernous, Central Nervous System genetics, Proto-Oncogene Proteins genetics, Tumor Suppressor Proteins genetics
- Abstract
When faced with an unusual clinical feature in a patient with a Mendelian disorder, the clinician may entertain the possibilities of either the feature representing a novel manifestation of that disorder or the co-existence of a different inherited condition. Here we describe an individual with a submandibular oncocytoma, pulmonary bullae and renal cysts as well as multiple cerebral cavernous malformations and haemangiomas. Genetic investigations revealed constitutional mutations in FLCN, associated with Birt-Hogg-Dubé syndrome (BHD) and CCM2, associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al. in Fam Cancer 14:595-597, 10.1007/s10689-015-9807-y , 2015) but it is not yet clear whether they represent a genuine part of that conditions' phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available. The increased use of next generation sequencing applications in diagnostic settings is likely to lead more cases such as this being revealed., Competing Interests: The authors declare that they have no conflict of interest. Informed consent Informed consent was obtained from all individual participants included in the study.
- Published
- 2017
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38. BRCA1/BRCA2 founder mutations and cancer risks: impact in the western Danish population.
- Author
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Nielsen HR, Nilbert M, Petersen J, Ladelund S, Thomassen M, Pedersen IS, Hansen TV, Skytte AB, Borg Å, and Therkildsen C
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms genetics, Cohort Studies, Denmark, Female, Genetic Predisposition to Disease, Genetics, Population, Humans, Male, Middle Aged, Ovarian Neoplasms genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Founder Effect, Neoplasms genetics
- Abstract
Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G>A and c.8474delC] were found to account for 23 % of the BRCA1 mutations and for 32 % of the BRCA2 mutations. The BRCA1 mutation c.3319G>T was, compared to other BRCA1 mutations, associated with a higher risk for ovarian cancer. In conclusion, founder mutations in BRCA1 and BRCA2 contribute to up to one-third of the families in western Denmark and among these the BRCA1 c.3319G>T mutation is potentially linked to an increased risk of ovarian cancer.
- Published
- 2016
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39. No evidence of increased breast cancer risk for proven noncarriers from BRCA1 and BRCA2 families.
- Author
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Nielsen HR, Petersen J, Krogh L, Nilbert M, and Skytte AB
- Subjects
- Aged, Case-Control Studies, Denmark, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics
- Abstract
In families screened for mutations in the BRCA1 or BRCA2 genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at above "average" risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female proven noncarriers in 239 BRCA1 and BRCA2 families compared with birth-matched controls from the Danish Civil Registration System. Prospective analysis showed no significantly increased risk for breast cancer in noncarriers with a hazard ratio of 0.67 [95 % confidence interval (CI) 0.32-1.42, p = 0.29] for all family members who tested negative and 0.87 (95 % CI 0.38-1.97, p = 0.73) for non-carries who were first-degree relatives of mutation carriers. Proven noncarriers from BRCA1 and BRCA2 families have no markedly increased risk for breast cancer compared to the general population, and our data do not suggest targeted breast cancer surveillance for noncarriers from BRCA1 and BRCA2 families.
- Published
- 2016
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40. Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients.
- Author
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Bennedbæk M, Rossing M, Rasmussen ÅK, Gerdes AM, Skytte AB, Jensen UB, Nielsen FC, and Hansen TVO
- Abstract
Background: Germline mutations in the succinate dehydrogenase complex genes SDHB, SDHC, and SDHD predispose to pheochromocytomas and paragangliomas. Here, we examine the SDHB, SDHC, and SDHD mutation spectrum in the Danish population by screening of 143 Danish pheochromocytoma and paraganglioma patients., Methods: Mutational screening was performed by Sanger sequencing or next-generation sequencing. The frequencies of variants of unknown clinical significance, e.g. intronic, missense, and synonymous variants, were determined using the Exome Aggregation Consortium database, while the significance of missense mutations was predicted by in silico and loss of heterozygosity analysis when possible., Results: We report 18 germline variants; nine in SDHB, six in SDHC, and three in SDHD. Of these 18 variants, eight are novel. We classify 12 variants as likely pathogenic/pathogenic, one as likely benign, and five as variants of unknown clinical significance., Conclusions: Identifying and classifying SDHB, SDHC, and SDHD variants present in the Danish population will augment the growing knowledge on variants in these genes and may support future clinical risk assessments.
- Published
- 2016
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41. Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review.
- Author
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Whitworth J, Skytte AB, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD, and Maher ER
- Subjects
- Adult, Aged, Alleles, Databases, Factual, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, MutS Homolog 2 Protein genetics, Proto-Oncogene Proteins genetics, Syndrome, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins genetics, Mutation, Neoplasms genetics
- Abstract
Mendelian causes of inherited cancer susceptibility are mostly rare and characterized by variable expression and incomplete penetrance. Phenotypic variability may result from a range of causes including locus heterogeneity, allelic heterogeneity, genetic and environmental modifier effects, or chance. Another potential cause is the presence of 2 or more inherited cancer predisposition alleles in the same individual. Although the frequency of such occurrences might be predicted to be low, such cases have probably been underascertained because standard clinical practice has been to test candidate inherited cancer genes sequentially until a pathogenic mutation is detected. However, recent advances in next-generation sequencing technologies now provide the opportunity to perform simultaneous parallel testing of large numbers of inherited cancer genes. Herein we provide examples of patients who harbor pathogenic mutations in multiple inherited cancer genes and review previously published examples to illustrate the complex genotype-phenotype relationships in these cases. We suggest that clinicians should proactively consider the likelihood of this phenomenon (referred to herein as multilocus inherited neoplasia alleles syndrome [MINAS]) in patients with unusual inherited cancer syndrome phenotypes. To facilitate the clinical management of novel cases of MINAS, we have established a database to collect information on what is likely to be an increasingly recognized cohort of such individuals.
- Published
- 2016
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42. The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.
- Author
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Depner M, Fuchs S, Raabe J, Frede N, Glocker C, Doffinger R, Gkrania-Klotsas E, Kumararatne D, Atkinson TP, Schroeder HW Jr, Niehues T, Dückers G, Stray-Pedersen A, Baumann U, Schmidt R, Franco JL, Orrego J, Ben-Shoshan M, McCusker C, Jacob CM, Carneiro-Sampaio M, Devlin LA, Edgar JD, Henderson P, Russell RK, Skytte AB, Seneviratne SL, Wanders J, Stauss H, Meyts I, Moens L, Jesenak M, Kobbe R, Borte S, Borte M, Wright DA, Hagin D, Torgerson TR, and Grimbacher B
- Subjects
- Adult, Candidiasis, Chronic Mucocutaneous genetics, Cells, Cultured, Cytokines metabolism, DNA Mutational Analysis, Female, Humans, Immunologic Deficiency Syndromes genetics, Male, Pedigree, Phenotype, Protein Structure, Tertiary genetics, STAT1 Transcription Factor genetics, Candidiasis, Chronic Mucocutaneous diagnosis, Immunologic Deficiency Syndromes diagnosis, Leukocytes, Mononuclear immunology, Mutation genetics, STAT1 Transcription Factor metabolism
- Abstract
Purpose: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients., Methods: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients., Results: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients., Conclusion: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
- Published
- 2016
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43. Increased risk of male cancer and identification of a potential prostate cancer cluster region in BRCA2.
- Author
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Roed Nielsen H, Petersen J, Therkildsen C, Skytte AB, and Nilbert M
- Subjects
- Age Factors, Aged, Breast Neoplasms, Male epidemiology, Denmark epidemiology, Family, Genetic Predisposition to Disease, Heterozygote, Humans, Male, Middle Aged, Neoplasm Grading, Prostatic Neoplasms epidemiology, Risk, Breast Neoplasms, Male genetics, Genes, BRCA1, Genes, BRCA2, Mutation, Prostatic Neoplasms genetics
- Abstract
Background: The risk of cancer in men from BRCA1 and BRCA2 families is relevant to define to motivate genetic testing and optimize recommendations for surveillance., Material and Methods: We assessed the risk of cancer in male mutation carriers and their first-degree relatives in 290 BRCA1 and BRCA2 families with comparison to matched controls with the aim to motivate genetic testing and optimize recommendations for surveillance., Results: Mutation carriers in BRCA1 families were not at increased risk of cancer, whereas mutation carriers in BRCA2 families were at increased risk of male breast cancer and prostate cancer with cumulative risks of 12.5% and 18.8%, respectively. Breast cancer developed at a mean age of 59 years, typically as ER/PR positive ductal carcinomas. Prostate cancer developed at a mean age of 68 years, with Gleason scores ≥ 8 in 40% of the tumors. The hazard ratio for BRCA2-associated prostate cancer was 3.7 (p < 0.001) in mutation carriers and 3.1 (p = 0.001) in first-degree relatives. Of the 37 prostate cancers, 19 were linked to four BRCA2 mutations within a region defined by c.6373-c.6492. Individuals with mutations herein had a HR of 3.7 for prostate cancer compared to individuals with mutations outside of this region., Conclusions: Male mutation carriers and first-degree relatives in BRCA2 families are at an increased risk of breast cancer and prostate cancer with a potential prostate cancer cluster region within exon 11 of BRCA2.
- Published
- 2016
- Full Text
- View/download PDF
44. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
- Author
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Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, Mazoyer S, Chenevix-Trench G, Easton DF, Antoniou AC, Nathanson KL, Laitman Y, Kushnir A, Paluch-Shimon S, Berger R, Zidan J, Friedman E, Ehrencrona H, Stenmark-Askmalm M, Einbeigi Z, Loman N, Harbst K, Rantala J, Melin B, Huo D, Olopade OI, Seldon J, Ganz PA, Nussbaum RL, Chan SB, Odunsi K, Gayther SA, Domchek SM, Arun BK, Lu KH, Mitchell G, Karlan BY, Walsh C, Lester J, Godwin AK, Pathak H, Ross E, Daly MB, Whittemore AS, John EM, Miron A, Terry MB, Chung WK, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Ejlertsen B, Gerdes AM, Hansen Tv, Ramón y Cajal T, Osorio A, Benitez J, Godino J, Tejada MI, Duran M, Weitzel JN, Bobolis KA, Sand SR, Fontaine A, Savarese A, Pasini B, Peissel B, Bonanni B, Zaffaroni D, Vignolo-Lutati F, Scuvera G, Giannini G, Bernard L, Genuardi M, Radice P, Dolcetti R, Manoukian S, Pensotti V, Gismondi V, Yannoukakos D, Fostira F, Garber J, Torres D, Rashid MU, Hamann U, Peock S, Frost D, Platte R, Evans DG, Eeles R, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Hodgson S, Morrison PJ, Walker L, Porteous ME, Kennedy MJ, Izatt L, Adlard J, Donaldson A, Ellis S, Sharma P, Schmutzler RK, Wappenschmidt B, Becker A, Rhiem K, Hahnen E, Engel C, Meindl A, Engert S, Ditsch N, Arnold N, Plendl HJ, Mundhenke C, Niederacher D, Fleisch M, Sutter C, Bartram CR, Dikow N, Wang-Gohrke S, Gadzicki D, Steinemann D, Kast K, Beer M, Varon-Mateeva R, Gehrig A, Weber BH, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Houdayer C, Belotti M, Gauthier-Villars M, Damiola F, Boutry-Kryza N, Lasset C, Sobol H, Peyrat JP, Muller D, Fricker JP, Collonge-Rame MA, Mortemousque I, Nogues C, Rouleau E, Isaacs C, De Paepe A, Poppe B, Claes K, De Leeneer K, Piedmonte M, Rodriguez G, Wakely K, Boggess J, Blank SV, Basil J, Azodi M, Phillips KA, Caldes T, de la Hoya M, Romero A, Nevanlinna H, Aittomäki K, van der Hout AH, Hogervorst FB, Verhoef S, Collée JM, Seynaeve C, Oosterwijk JC, Gille JJ, Wijnen JT, Gómez Garcia EB, Kets CM, Ausems MG, Aalfs CM, Devilee P, Mensenkamp AR, Kwong A, Olah E, Papp J, Diez O, Lazaro C, Darder E, Blanco I, Salinas M, Jakubowska A, Lubinski J, Gronwald J, Jaworska-Bieniek K, Durda K, Sukiennicki G, Huzarski T, Byrski T, Cybulski C, Toloczko-Grabarek A, Złowocka-Perłowska E, Menkiszak J, Arason A, Barkardottir RB, Simard J, Laframboise R, Montagna M, Agata S, Alducci E, Peixoto A, Teixeira MR, Spurdle AB, Lee MH, Park SK, Kim SW, Friebel TM, Couch FJ, Lindor NM, Pankratz VS, Guidugli L, Wang X, Tischkowitz M, Foretova L, Vijai J, Offit K, Robson M, Rau-Murthy R, Kauff N, Fink-Retter A, Singer CF, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Berger A, Greene MH, Mai PL, Imyanitov EN, Toland AE, Senter L, Bojesen A, Pedersen IS, Skytte AB, Sunde L, Thomassen M, Moeller ST, Kruse TA, Jensen UB, Caligo MA, Aretini P, Teo SH, Selkirk CG, Hulick PJ, and Andrulis I
- Subjects
- Adult, Age of Onset, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Mutation, Ovarian Neoplasms genetics
- Abstract
Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists., Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2., Design, Setting, and Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk., Exposures: Mutations of BRCA1 or BRCA2., Main Outcomes and Measures: Breast and ovarian cancer risks., Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers., Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
- Published
- 2015
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45. Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.
- Author
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Carvalho CM, Vasanth S, Shinawi M, Russell C, Ramocki MB, Brown CW, Graakjaer J, Skytte AB, Vianna-Morgante AM, Krepischi AC, Patel GS, Immken L, Aleck K, Lim C, Cheung SW, Rosenberg C, Katsanis N, and Lupski JR
- Subjects
- Acyl-CoA Dehydrogenase, Long-Chain genetics, Adaptor Proteins, Signal Transducing genetics, Animals, Apoptosis Regulatory Proteins, Asialoglycoprotein Receptor genetics, Base Sequence, Cell Line, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, Pair 17 genetics, Dishevelled Proteins, Flow Cytometry, Humans, Immunohistochemistry, Microtubule-Associated Proteins genetics, Molecular Sequence Data, Phosphoproteins genetics, Retrospective Studies, Sequence Analysis, DNA, Smith-Magenis Syndrome, Syndrome, Zebrafish, Abnormalities, Multiple genetics, Gene Dosage genetics, Intellectual Disability genetics, Microcephaly genetics
- Abstract
The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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46. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.
- Author
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Bancroft EK, Page EC, Castro E, Lilja H, Vickers A, Sjoberg D, Assel M, Foster CS, Mitchell G, Drew K, Mæhle L, Axcrona K, Evans DG, Bulman B, Eccles D, McBride D, van Asperen C, Vasen H, Kiemeney LA, Ringelberg J, Cybulski C, Wokolorczyk D, Selkirk C, Hulick PJ, Bojesen A, Skytte AB, Lam J, Taylor L, Oldenburg R, Cremers R, Verhaegh G, van Zelst-Stams WA, Oosterwijk JC, Blanco I, Salinas M, Cook J, Rosario DJ, Buys S, Conner T, Ausems MG, Ong KR, Hoffman J, Domchek S, Powers J, Teixeira MR, Maia S, Foulkes WD, Taherian N, Ruijs M, Helderman-van den Enden AT, Izatt L, Davidson R, Adank MA, Walker L, Schmutzler R, Tucker K, Kirk J, Hodgson S, Harris M, Douglas F, Lindeman GJ, Zgajnar J, Tischkowitz M, Clowes VE, Susman R, Ramón y Cajal T, Patcher N, Gadea N, Spigelman A, van Os T, Liljegren A, Side L, Brewer C, Brady AF, Donaldson A, Stefansdottir V, Friedman E, Chen-Shtoyerman R, Amor DJ, Copakova L, Barwell J, Giri VN, Murthy V, Nicolai N, Teo SH, Greenhalgh L, Strom S, Henderson A, McGrath J, Gallagher D, Aaronson N, Ardern-Jones A, Bangma C, Dearnaley D, Costello P, Eyfjord J, Rothwell J, Falconer A, Gronberg H, Hamdy FC, Johannsson O, Khoo V, Kote-Jarai Z, Lubinski J, Axcrona U, Melia J, McKinley J, Mitra AV, Moynihan C, Rennert G, Suri M, Wilson P, Killick E, Moss S, and Eeles RA
- Subjects
- Adult, Aged, Biopsy, Genotype, Humans, Male, Middle Aged, Patient Selection, Predictive Value of Tests, Prostatic Neoplasms blood, Early Detection of Cancer, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease genetics, Mutation, Prostate pathology, Prostate-Specific Antigen blood, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Background: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations., Objective: To report the first year's screening results for all men at enrollment in the study., Design, Setting and Participants: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy., Outcome Measurements and Statistical Analysis: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types., Results and Limitations: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups., Conclusions: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease., Patient Summary: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment., (Copyright © 2014 European Association of Urology. All rights reserved.)
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- 2014
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47. [Molecular genetic screening for polycystic kidney disease can be an important diagnostic tool].
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Rasmussen M, Ørskov B, Skytte AB, and Sunde L
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- Child, Child, Preschool, Female, Genetic Testing, Humans, Magnetic Resonance Imaging, Male, Mutation, TRPP Cation Channels genetics, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is associated with mutation in the PKD1- or PKD2-gene. We present two cases with an atypical presentation of ADPKD. Molecular genetic screening of PKD1 and PKD2 confirmed the diagnoses. Screening of PKD1 and PKD2 has become an important diagnostic tool.
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- 2014
48. [Cowden syndrome can be a challenging diagnosis].
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Skytte AB, Gerdes AM, and Bygum A
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- Germ-Line Mutation, Hamartoma Syndrome, Multiple complications, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple pathology, Hand pathology, Humans, Practice Guidelines as Topic, Hamartoma Syndrome, Multiple diagnosis, PTEN Phosphohydrolase genetics
- Abstract
Cowden syndrome is a rare autosomal dominant overgrowth syndrome with a predisposition to cancer. The overgrowth and cancer may occur in many different tissues, which makes it a challenge to recognize it, but due to the high risk of cancer early diagnosis is important. We present the Danish screening guidelines for patients with Cowden syndrome.
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- 2014
49. [Cowden syndrome diagnosed in patients with macrocephaly].
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Skytte AB, Bojesen A, and Bygum A
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- Adult, Cephalometry, Female, Genetic Predisposition to Disease, Goiter diagnosis, Hamartoma Syndrome, Multiple genetics, Hamartoma Syndrome, Multiple pathology, Humans, Keratoderma, Palmoplantar pathology, Male, Megalencephaly diagnosis, Middle Aged, Mutation, PTEN Phosphohydrolase genetics, Warts diagnosis, Hamartoma Syndrome, Multiple diagnosis
- Abstract
Cowden syndrome is a rare autosomal dominant syndrome with a predisposition to cancer. We present a case of Cowden syndrome in a mother and her son, who were diagnosed with palmoplantar hyperkeratosis, macrocephaly and goitre. Early diagnosis is a challenge as the patients present with a variety of symptoms, but it is important because of the risk of cancer.
- Published
- 2014
50. UBE2QL1 is disrupted by a constitutional translocation associated with renal tumor predisposition and is a novel candidate renal tumor suppressor gene.
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Wake NC, Ricketts CJ, Morris MR, Prigmore E, Gribble SM, Skytte AB, Brown M, Clarke N, Banks RE, Hodgson S, Turnell AS, Maher ER, and Woodward ER
- Subjects
- Adult, Base Sequence, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic genetics, Chromosome Breakpoints, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, DNA Methylation, Epigenesis, Genetic, F-Box Proteins metabolism, F-Box-WD Repeat-Containing Protein 7, Female, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms metabolism, Molecular Sequence Data, Protein Binding, Protein Transport, Ubiquitin-Conjugating Enzymes chemistry, Ubiquitin-Conjugating Enzymes metabolism, Ubiquitin-Protein Ligases metabolism, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Kidney Neoplasms genetics, Translocation, Genetic, Ubiquitin-Conjugating Enzymes genetics
- Abstract
Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gene., (© 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
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