Simple SummaryAlthough granulosa cell tumors can occur in rare syndromes and one familial case of a granulosa cell tumor has been described, a genetic predisposition for granulosa cell tumors has... Show moreSimple SummaryAlthough granulosa cell tumors can occur in rare syndromes and one familial case of a granulosa cell tumor has been described, a genetic predisposition for granulosa cell tumors has not been identified. Through our collaborations with patients, we identified four families in which two women of each family were diagnosed with an adult granulosa cell tumor. Although predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were found, we could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for granulosa cell tumors. The age of onset in the familial patients was significantly lower (median 38 years, range from 17 to 60) than in sporadic patients (median between 50 and 55 years). Furthermore, breast cancer, polycystic ovary syndrome, and subfertility were seen in these families.Adult granulosa cell tumor (AGCT) is a rare ovarian cancer subtype, with a peak incidence around 50-55 years. Although AGCT can occur in specific syndromes, a genetic predisposition for AGCT has not been identified. The aim of this study is to identify a genetic variant in families with AGCT patients, potentially contributing to tumor evolution. We identified four families, each including two women diagnosed with AGCT. Whole-genome sequencing was performed to identify overlapping germline variants or affected genes. Familial relationship was evaluated using genealogy and genomic analyses. Patient characteristics, medical (family) history, and pedigrees were collected. Findings were compared to a reference group of 33 unrelated AGCT patients. Mean age at diagnosis was 38 years (range from 17 to 60) versus 51 years in the reference group, and seven of eight patients were premenopausal. In two families, three first degree relatives were diagnosed with breast cancer. Furthermore, polycystic ovary syndrome (PCOS) and subfertility was reported in three families. Predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were identified. In conclusion, AGCTs occur in families and could potentially be hereditary. In these families, the age of AGCT diagnosis is lower and cases of breast cancer, PCOS, and subfertility are present. We could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for AGCT. Show less
BackgroundHearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the... Show moreBackgroundHearing loss is one of the most prevalent disabilities worldwide, and has a significant impact on quality of life. The adult-onset type of the condition is highly heritable but the genetic causes are largely unknown, which is in contrast to childhood-onset hearing loss.MethodsFamily and cohort studies included exome sequencing and characterisation of the hearing phenotype. Ex vivo protein expression addressed the functional effect of a DNA variant.ResultsAn in-frame deletion of 12 nucleotides in RIPOR2 was identified as a highly penetrant cause of adult-onset progressive hearing loss that segregated as an autosomal dominant trait in 12 families from the Netherlands. Hearing loss associated with the deletion in 63 subjects displayed variable audiometric characteristics and an average (SD) age of onset of 30.6 (14.9) years (range 0-70 years). A functional effect of the RIPOR2 variant was demonstrated by aberrant localisation of the mutant RIPOR2 in the stereocilia of cochlear hair cells and failure to rescue morphological defects in RIPOR2-deficient hair cells, in contrast to the wild-type protein. Strikingly, the RIPOR2 variant is present in 18 of 22 952 individuals not selected for hearing loss in the Southeast Netherlands.ConclusionCollectively, the presented data demonstrate that an inherited form of adult-onset hearing loss is relatively common, with potentially thousands of individuals at risk in the Netherlands and beyond, which makes it an attractive target for developing a (genetic) therapy. Show less
Purpose While neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many... Show morePurpose While neonatal bloodspot screening (NBS) for severe combined immunodeficiency (SCID) has been introduced more than a decade ago, implementation in NBS programs remains challenging in many countries. Even if high-quality test methods and follow-up care are available, public uptake and parental acceptance are not guaranteed. The aim of this study was to describe the parental perspective on NBS for SCID in the context of an implementation pilot. Psychosocial aspects have never been studied before for NBS for SCID and are important for societal acceptance, a major criterion when introducing new disorders in NBS programs. Methods To evaluate the perspective of parents, interviews were conducted with parents of newborns with abnormal SCID screening results (N = 17). In addition, questionnaires about NBS for SCID were sent to 2000 parents of healthy newborns who either participated or declined participation in the SONNET-study that screened 140,593 newborns for SCID. Results Support for NBS for SCID was expressed by the majority of parents in questionnaires from both a public health perspective and a personal perspective. Parents emphasized the emotional impact of an abnormal screening result in interviews. (Long-term) stress and anxiety can be experienced during and after referral indicating the importance of uniform follow-up protocols and adequate information provision. Conclusion The perspective of parents has led to several recommendations for NBS programs that are considering screening for SCID or other disorders. A close partnership of NBS programs' stakeholders, immunologists, geneticists, and pediatricians-immunologists in different countries is required for moving towards universal SCID screening for all infants. Show less
Dit proefschrift beschrijft het onderzoek naar de stabiliteit van twee typen DNA volgordes (sequenties) die vaak voorkomen in DNA: microsatellieten en G-quadruplex sequenties. Microsatellieten zijn... Show moreDit proefschrift beschrijft het onderzoek naar de stabiliteit van twee typen DNA volgordes (sequenties) die vaak voorkomen in DNA: microsatellieten en G-quadruplex sequenties. Microsatellieten zijn kleine stukjes repeterend DNA en G-quadruplex sequenties hebben de unieke eigenschap om een DNA-structuur te vormen die bestaat uit vier DNA-strengen. Bij een celdeling, waarbij het DNA gekopieerd moet worden, blijken deze twee sequenties soms lastig te kopi_ren te zijn. Dit kan tot DNA-instabiliteit leiden. Deze instabiliteit wordt in verband gebracht met kanker en neurodegeneratieve ziektes zoals ALS. Het is daarom van groot belang om alles te weten te komen over microsatelliet- en G-quadruplex-instabiliteit. Allereerst worden in dit proefschrift nieuwe methodes beschreven waarmee de instabiliteit van microsatellieten en G-quadruplexes makkelijk kan worden waargenomen. Met behulp van deze methodes zijn vervolgens verschillende ontdekkingen gedaan. Zo is bijvoorbeeld ontdekt dat in menselijke cellen een klein RNA-molecuul betrokken is bij het instabiel worden van microsatellieten en het ontstaan van darmkanker. Een ander belangrijke bevinding is de ontdekking van een nieuw soort DNA-reparatie mechanisme in de rondworm. De ontdekking van dit mechanisme, waarbij het eiwit polymerase theta G-quadruplex-ge_nduceerde DNA schade repareert, heeft tot nieuwe inzichten geleid op het gebied van genetische mutaties, evolutie en het bestrijden van tumoren. Show less
Bosch, P.C.; Segura-Bayona, S.; Koole, W.; Heteren, J.T. van; Dewar, J.M.; Tijsterman, M.; Knipscheer, P. 2014
