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Article ; Online: Clinically-relevant Germline Variants in Children with Non-Medullary Thyroid Cancer.

van der Tuin, Karin / Ruano, Dina / Knijnenburg, Jeroen / van der Luijt, Rob B / Morreau, Hans / Links, Thera P / Hes, Frederik J

The Journal of clinical endocrinology and metabolism

2024

Abstract: Context: The underlying genetic cause of non-medullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management.: Objective: Our objectives were to investigated the ... ...

Abstract	Context: The underlying genetic cause of non-medullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management. Objective: Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date. Design: Nationwide retrospective cohort study. Setting: Tertiary referral centers. Patients: In total, 97 patients diagnosed with pediatric NMTC between 1970-2020 were included in this study. Intervention: Germline whole genome sequencing (WGS). Main outcome: The main outcome measures were mutation detection yield in 1) clinically-relevant tumor predisposition genes, and 2) genes previously associated with NMTC. Results: In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic (P/LP) variant in a well-known tumor predisposition gene: APC (n=1), BRCA2 (n=2), CHEK2 (n=4), DICER1 (n=4), HOXB13 (n=1), , and MITF (n=1). In addition, one patient was diagnosed with Pendred syndrome (SLC26A4) and nine variants of high interest were found in other NMTC candidate susceptibility genes. Conclusion: The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal-/family history and histology led us to recommend genetic counseling for all childhood NMTC patients.The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and pre-symptomatic genetic testing of at risk family members.
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgae107
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Article ; Online: Are disease-specific patient-reported outcomes measures (PROMs) used in cardiogenetics? A systematic review.

van Pottelberghe, Saar / Kupper, Nina / Scheirlynck, Esther / Amin, Ahmad S / Wilde, Arthur A M / Hofman, Nynke / Callus, Edward / Biller, Ruth / Nekkebroeck, Julie / Van Dooren, Sonia / Hes, Frederik J / van der Crabben, Saskia N

European journal of human genetics : EJHG

2023

Abstract: Patient-reported outcome measures (PROMs) are used to facilitate patient-centered care (PCC). While studies in patients with cardiac conditions have revealed poorer health-related quality of life (HRQoL) and elevated emotional stress, studies in ... ...

Abstract	Patient-reported outcome measures (PROMs) are used to facilitate patient-centered care (PCC). While studies in patients with cardiac conditions have revealed poorer health-related quality of life (HRQoL) and elevated emotional stress, studies in inherited cardiac conditions (ICC) seem rare. A systematic review evaluated which (specific domains of) PROMs are used in patients with ICC. From three databases (PubMed, PsychINFO, and Web of Science) quantitative studies investigating PROMs in patients with ICC were included. A Cochrane-based assessment tool was used to evaluate quality and potential risk of bias per subdomain. Data from 17 eligible articles were extracted. Among the included studies, risk of bias was predominantly high (35%) or unclear (30%). Most (n = 14) studies used a generic health status measure (SF-36, SF-12); 3 studies used a disease-specific PROM (KCCQ- cardiomyopathy and MLFHQ-heart failure). In addition to HRQoL measures, several studies used affective psychological measures (i.e., HADS, CAQ-18, IES-R, and IPQ). The mental health component of the PROMs showed lower scores overall in patients with ICC compared to population norms. Nine studies using HADS and GAD-7/PHQ-9 showed a prevalence of clinically significant anxiety (17-47%) and depression levels (8.3-28%) that were higher than the population norm (8.3% and 6.3%, respectively). HRQoL in patients with ICC is primarily assessed with generic PROMs. Results further confirmed high psychological morbidity in this population. Generic PROMS measures evaluate overall health status, but lack sensitivity to ICC-specific factors like heredity-related concerns. We propose developing a PROM specific for ICC to optimize PCC.
Language	English
Publishing date	2023-12-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-023-01510-w
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Zs.A 3589: Show issues

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Article ; Online: Use of sanger and next-generation sequencing to screen for mosaic and intronic APC variants in unexplained colorectal polyposis patients.

Elsayed, Fadwa A / Tops, Carli M J / Nielsen, Maartje / Morreau, Hans / Hes, Frederik J / van Wezel, Tom

Familial cancer

2021 Volume 21, Issue 1, Page(s) 79–83

Abstract: In addition to classic germline APC gene variants, APC mosaicism and deep intronic germline APC variants have also been reported to be causes of adenomatous polyposis. In this study, we investigated 80 unexplained colorectal polyposis patients without ... ...

Abstract	In addition to classic germline APC gene variants, APC mosaicism and deep intronic germline APC variants have also been reported to be causes of adenomatous polyposis. In this study, we investigated 80 unexplained colorectal polyposis patients without germline pathogenic variants in known polyposis predisposing genes to detect mosaic and deep intronic APC variants. All patients developed more than 50 colorectal polyps, with adenomas being predominantly observed. To detect APC mosaicism, we performed next-generation sequencing (NGS) in leukocyte DNA. Furthermore, using Sanger sequencing, the cohort was screened for the following previously reported deep intronic pathogenic germline APC variants: c.1408 + 731C > T, p.(Gly471Serfs55), c.1408 + 735A > T, p.(Gly471Serfs55), c.1408 + 729A > G, p.(Gly471Serfs55) and c.532-941G > A, p.(Phe178Argfs22). We did not detect mosaic or intronic APC variants in the screened unexplained colorectal polyposis patients. The results of this study indicate that the deep intronic APC variants investigated in this study are not a cause of colorectal polyposis in this Dutch population. In addition, NGS did not detect any further mosaic variants in our cohort.
MeSH term(s)	Adenomatous Polyposis Coli/genetics ; Adenomatous Polyposis Coli/pathology ; Adenomatous Polyposis Coli Protein/genetics ; Colorectal Neoplasms/genetics ; Genes, APC ; Germ-Line Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation
Chemical Substances	Adenomatous Polyposis Coli Protein
Language	English
Publishing date	2021-03-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1502496-9
ISSN	1573-7292 ; 1389-9600
ISSN (online)	1573-7292
ISSN	1389-9600
DOI	10.1007/s10689-021-00236-2
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Zs.A 6099: Show issues

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Article ; Online: Lynch syndrome: still not a familiar picture.

Hes, Frederik J

World journal of surgical oncology

2008 Volume 6, Page(s) 21

Abstract: Background: Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems.: Case presentation: A large Lynch syndrome family with 15 affected family ... ...

Abstract	Background: Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems. Case presentation: A large Lynch syndrome family with 15 affected family members and involvement in 7 organs is reported. It illustrates a lack of awareness and knowledge about this hereditary tumor syndrome among doctors as well as patients. None of the described family members underwent presymptomatic screening on the basis of the family history. Conclusion: Hereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, should lead to timely referral of suspected cases for genetic counseling and diagnostics. For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria. Subsequently, early identification of mutation carriers might have diminished, at least in part, the high and early morbidity and mortality observed in this family.
MeSH term(s)	Adenocarcinoma ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/epidemiology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Female ; Genetic Diseases, Inborn ; Humans ; Middle Aged ; Mutation
Language	English
Publishing date	2008-02-20
Publishing country	England
Document type	Case Reports ; Journal Article
ZDB-ID	2118383-1
ISSN	1477-7819 ; 1477-7819
ISSN (online)	1477-7819
ISSN	1477-7819
DOI	10.1186/1477-7819-6-21
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Article ; Online: APC

Terlouw, Diantha / Hes, Frederik J / Suerink, Manon / Boot, Arnoud / Langers, Alexandra M J / Tops, Carli M / van Leerdam, Monique E / van Asperen, Christi J / Rozen, Steve G / Bijlsma, Emilia K / van Wezel, Tom / Morreau, Hans / Nielsen, Maartje

Gut

2022 Volume 72, Issue 11, Page(s) 2186–2187

MeSH term(s)	Humans ; Mosaicism ; Adenomatous Polyposis Coli/diagnosis ; Adenomatous Polyposis Coli/genetics ; Genes, APC ; Adenomatous Polyposis Coli Protein/genetics ; Colorectal Neoplasms/genetics ; Germ-Line Mutation ; Mutation
Chemical Substances	Adenomatous Polyposis Coli Protein
Language	English
Publishing date	2022-10-28
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2022-328540
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Zs.A 160: Show issues

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Article ; Online: Estimating the penetrance of pathogenic gene variants in families with missing pedigree information.

Jonker, Marianne A / Rijken, Johannes A / Hes, Frederik J / Putter, Hein / Hensen, Erik F

Statistical methods in medical research

2018 Volume 28, Issue 10-11, Page(s) 2924–2936

Abstract: Accurate assessment of the age-dependent disease risk conferred by germline variants in disease susceptibility genes is often hampered by the way the data are collected. Cohort-based data sets frequently contain an overrepresentation of patients (i.e. ... ...

Abstract	Accurate assessment of the age-dependent disease risk conferred by germline variants in disease susceptibility genes is often hampered by the way the data are collected. Cohort-based data sets frequently contain an overrepresentation of patients (i.e. carriers of the gene variant of interest affected with the associated disease), and an underrepresentation of disease-free carriers. In order to overcome this problem, penetrance estimates can be based on family-based study designs, through the evaluation of index patients and their family members. This approach facilitates the identification of asymptomatic germline variant carriers. By adjusting for the way these family data are ascertained, an estimate for the penetrance of the pathogenic gene variant can be obtained. However, the family structure is often incomplete or missing. This complicates the estimation of the penetrance, because full adjustment of the likelihood is not possible. We present a conditional likelihood for the estimation of the penetrance of pathogenic gene variants, based on a cohort of multiple families comprising index patients, disease-free and affected non-index carriers, but with missing information on pedigree structure. The proposed estimator corrects for the ascertainment in a robust way and is shown to be more accurate than the frequently used Kaplan-Meier estimator of the penetrance function.
MeSH term(s)	Aged ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Germ-Line Mutation ; Humans ; Male ; Middle Aged ; Models, Genetic ; Pedigree ; Penetrance
Language	English
Publishing date	2018-08-03
Publishing country	England
Document type	Journal Article
ZDB-ID	1136948-6
ISSN	1477-0334 ; 0962-2802
ISSN (online)	1477-0334
ISSN	0962-2802
DOI	10.1177/0962280218791338
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Zs.A 3564: Show issues

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Article ; Online: Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis.

Aretz, Stefan / Hes, Frederik J

European journal of human genetics : EJHG

2010 Volume 18, Issue 9

MeSH term(s)	Adenomatous Polyposis Coli/diagnosis ; Adenomatous Polyposis Coli/genetics ; DNA Glycosylases/genetics ; Genes, Recessive ; Humans ; Mutation ; Sensitivity and Specificity
Chemical Substances	DNA Glycosylases (EC 3.2.2.-) ; mutY adenine glycosylase (EC 3.2.2.-)
Language	English
Publishing date	2010-05-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/ejhg.2010.77
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Article ; Online: Adaptive magnetic resonance-guided neurovascular-sparing radiotherapy for preservation of erectile function in prostate cancer patients.

Teunissen, Frederik R / Wortel, Ruud C / Hes, Jochem / Willigenburg, Thomas / de Groot-van Breugel, Eline N / de Boer, Johannes C J / van Melick, Harm H E / Verkooijen, Helena M / van der Voort van Zyp, Jochem R N

Physics and imaging in radiation oncology

2021 Volume 20, Page(s) 5–10

Abstract: Background and purpose: Erectile dysfunction is a common adverse effect of external beam radiation therapy for localized prostate cancer (PCa), likely as a result of damage to neural and vascular tissue. Magnetic resonance-guided online adaptive ... ...

Abstract	Background and purpose: Erectile dysfunction is a common adverse effect of external beam radiation therapy for localized prostate cancer (PCa), likely as a result of damage to neural and vascular tissue. Magnetic resonance-guided online adaptive radiotherapy (MRgRT) enables high-resolution MR imaging and paves the way for neurovascular-sparing approaches, potentially lowering erectile dysfunction after radiotherapy for PCa. The aim of this study was to assess the planning feasibility of neurovascular-sparing MRgRT for localized PCa. Materials and methods: Twenty consecutive localized PCa patients, treated with standard 5×7.25 Gy MRgRT, were included. For these patients, neurovascular-sparing 5×7.25 Gy MRgRT plans were generated Results: Neurovascular-sparing constraints for the CC, and PB were met in all 20 patients. For the IPA, constraints were met in 19 (95%) patients bilaterally and 1 (5%) patient unilaterally. Constraints for the NVB were met in 8 (40%) patients bilaterally, in 8 (40%) patients unilaterally, and were not met in 4 (20%) patients. NVB constraints were not met when gross tumor volume (GTV) was located dorsolaterally in the prostate. Dose to the NVB, IPA, and CC was significantly lower in the neurovascular-sparing plans. Conclusions: Neurovascular-sparing MRgRT for localized PCa is feasible in the planning setting. The extent of NVB sparing largely depends on the patient's GTV location in relation to the NVB.
Language	English
Publishing date	2021-09-21
Publishing country	Netherlands
Document type	Journal Article
ISSN	2405-6316
ISSN (online)	2405-6316
DOI	10.1016/j.phro.2021.09.002
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Article ; Online: A systematic review and evidence assessment of monogenic gene-disease relationships in human female infertility and differences in sex development.

Van Der Kelen, Annelore / Okutman, Özlem / Javey, Elodie / Serdarogullari, Münevver / Janssens, Charlotte / Ghosh, Manjusha S / Dequeker, Bart J H / Perold, Florence / Kastner, Claire / Kieffer, Emmanuelle / Segers, Ingrid / Gheldof, Alexander / Hes, Frederik J / Sermon, Karen / Verpoest, Willem / Viville, Stéphane

Human reproduction update

2022 Volume 29, Issue 2, Page(s) 218–232

Abstract: Background: As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified ... ...

Abstract	Background: As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene-disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases. Objective and rationale: An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR. Search methods: PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR. Outcomes: A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility. Wider implications: We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.
MeSH term(s)	Humans ; Male ; Female ; Infertility, Female/genetics ; Phenotype ; Genetic Counseling ; Sexual Development
Language	English
Publishing date	2022-12-09
Publishing country	England
Document type	Systematic Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1286738-x
ISSN	1460-2369 ; 1355-4786
ISSN (online)	1460-2369
ISSN	1355-4786
DOI	10.1093/humupd/dmac044
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Zs.A 4378: Show issues

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Article ; Online: Lynch syndrome

Hes Frederik J

World Journal of Surgical Oncology, Vol 6, Iss 1, p

still not a familiar picture

2008 Volume 21

Abstract: Abstract Background Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems. Case presentation A large Lynch syndrome family with 15 affected ... ...

Abstract	Abstract Background Germ line mutations in mismatch repair genes underlie Lynch syndrome and predispose carriers for colorectal carcinoma and malignancies in many other organ systems. Case presentation A large Lynch syndrome family with 15 affected family members and involvement in 7 organs is reported. It illustrates a lack of awareness and knowledge about this hereditary tumor syndrome among doctors as well as patients. None of the described family members underwent presymptomatic screening on the basis of the family history. Conclusion Hereditary features, like young age at diagnosis, multiple tumors in multiple organs and a positive family history, should lead to timely referral of suspected cases for genetic counseling and diagnostics. For Lynch syndrome, these features can be found in the Amsterdam and Bethesda criteria. Subsequently, early identification of mutation carriers might have diminished, at least in part, the high and early morbidity and mortality observed in this family.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2008-02-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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