Center for Medical Genetics

Osnabrück, Germany

Center for Medical Genetics

Osnabrück, Germany

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Belva F.,Center for Medical Genetics | Roelants M.,Vrije Universiteit Brussel | De Schepper J.,UZ Brussel | Roseboom T.J.,Clinical Epidemiology and Biostatistics | And 3 more authors.
Human Reproduction | Year: 2012

STUDY QUESTIONDo young adolescents conceived by ICSI display a higher blood pressure than spontaneously conceived (SC) adolescents? SUMMARY ANSWERIn our study, 14-year-old male and female ICSI teenagers were not found to have increased blood pressure at rest. WHAT IS KNOWN AND WHAT THIS PAPER ADDSOnly limited data are available regarding the cardiovascular risk of children born after assisted conception and up till now, no data on the cardiovascular health in pubertal children conceived by ICSI have been published. In this study, resting blood pressure and blood pressure response to a psychological stressor were measured in a cohort of 14-year-old teenagers conceived by ICSI and compared the results with those of a group of SC peers. DESIGNIn this cross-sectional study, resting blood pressure measurements were available from 217 singleton ICSI children (116 boys, 101 girls) and 223 singleton control children born after spontaneous conception (115 boys, 108 girls). Continuous blood pressure measurements, performed during a psychological stress test, were available for only 67 ICSI and 38 SC children. PARTICIPANTS AND SETTINGThe study group comprised adolescents conceived by ICSI predominantly because of male factor infertility and they were part of a previously published cohort followed since birth; controls were a cross-sectional sample of peers born to fertile parents and recruited from comparable schools as those attended by the ICSI teenagers. Response rates were 56 (tested/reached) in the ICSI group and 50 (agreed/eligible) in the SC group, but information regarding health could be obtained in 63 and 72 of the ICSI and SC children, respectively. MAIN RESULTS AND THE ROLE OF CHANCEICSI girls had a comparable resting systolic (109 ± 9 mmHg) and diastolic (64 ± 6 mmHg) blood pressure in comparison with girls in the SC group (111 ± 9 mmHg, P=0.2 and 66 ± 7 mmHg, P=0.05), even after adjustment for age and height. After adjustment for current body characteristics, early life and parental BACKGROUNDBACKGROUND factors, systolic and diastolic blood pressure remained comparable in both groups. In ICSI boys, a slightly lower systolic (113 ± 10 mmHg), but comparable diastolic (64 ± 6 mmHg) resting blood pressure was found in comparison with the SC group (116 ± 9 mmHg; P=0.04 and 65 ± 5 mmHg; P=0.1). After adjustment for height and age, systolic and diastolic blood pressure were comparable in both groups (P=0.7 and P=0.6). After correction for current body characteristics, early life and parental factors, ICSI and SC boys still had comparable systolic (difference in ICSI versus SC:-1.1 mmHg; 95 CI:-3.81.6; P=0.4) and diastolic (difference in ICSI versus SC:-1.2 mmHg; 95 CI:-3.20.7; P=0.2) blood pressure measurements. In the small subsample of girls and boys with continuous blood pressure readings, the systolic and diastolic blood pressure response to the stress test was not significantly different between the ICSI and SC groups even after taking into account the baseline values. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTIONDespite the rather low response rate in the ICSI group and the fact that no information on current health status could be obtained from more than a quarter of the eligible comparison group, the non-participating analysis in the ICSI as well in the SC group did not reveal differences between participating and non-participating children regarding clinical characteristics. The negative results for the sub-analysis on blood pressure response to stress should be interpreted with caution, because these data were available for only a small number of children, and the analysis may be underpowered. This result can only rule out a large effect on blood pressure responsiveness to a psychological stressor. Although our sample size appears to be appropriate, our results need confirmation by others and in larger cohorts when more data become available. GENERALIZABILITY TO OTHER POPULATIONSOur results are the first described ever in ICSI offspring, born to parents suffering from predominantly male factor infertility. STUDY FUNDING/COMPETING INTEREST(S)This study was supported by research grants from Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Onderzoeksraad Vrije Universiteit Brussel and Wetenschappelijk Fonds Willy Gepts. Unconditional grants from MSD Belgium, Merck International, IBSA Institut Biochimique and Ferring International Center are kindly acknowledged. © 2012 The Author.


Belva F.,Center for Medical Genetics | Painter R.,AMC | Bonduelle M.,Center for Medical Genetics | Roelants M.,Vrije Universiteit Brussel | And 2 more authors.
Human Reproduction | Year: 2012

BACKGROUND: Puberty is a critical period for the development of cardio-metabolic disturbances, including a more central body fat distribution. It is still unclear if IVF and more specifically ICSI, can permanently and detrimentally affect body fat accumulation in the human offspring. Therefore, adiposity and body fat distribution in 14-year-old adolescents born after ICSI were investigated. METHODS: Body composition data, including anthropometry (weight, height and BMI), skinfold thicknesses (peripheral: triceps and biceps skinfolds; central: supra-iliacal and subscapular skinfolds; total: sum of the four skinfolds) and circumferences (waist, mid-upper arm) were compared between 217 ICSI singletons (116 boys, 101 girls) and 223 singletons (115 boys, 108 girls) born after spontaneous conception (SC). ICSI teenagers were part of a previously published ICSI cohort followed since birth; SC controls were recruited from schools in the surroundings. RESULTS: Among all boys, no differences in body composition measurements were found between the ICSI and SC group, taking into account confounding variables. In boys with more advanced pubertal stages, a significantly higher sum of peripheral skinfolds was found in the ICSI group compared with the SC group (difference 3.5 mm, 95 confidence interval 0.36.6). In girls, peripheral adiposity assessed by skinfolds and mid-upper arm circumference, and central adiposity assessed by skinfolds and waist circumference as well as total adiposity assessed by BMI, the sum of four skinfold thicknesses and skinfold-derived body fat percentage were significantly higher in the ICSI group compared with the SC group, taking into account confounding variables (all P< 0.05). Neither parental nor early life factors could explain the differences. CONCLUSIONS: We found that pubertal ICSI girls were more prone to central, peripheral and total adiposity compared with their SC counterparts. ICSI adolescents with advanced pubertal stages showed more peripheral adiposity. Continued monitoring of body fat patterns in adolescents born after fertility treatment is mandatory in order to assess their risk for developing obesity and its related adverse health effects in adulthood. © The Author 2011.


Belva F.,Center for Medical Genetics | Bonduelle M.,Center for Medical Genetics | Painter R.C.,AMC | Schiettecatte J.,Laboratory Clinical Chemistry and Radioimmunology Laboratory | And 2 more authors.
Human Reproduction | Year: 2010

Background Currently, no published data exist about the gonadal function of children born after ICSI. To evaluate potential risk of testicular seminal dysfunction in boys born to fathers with compromised spermatogenesis, serum inhibin B (as a marker for spermatogenesis) was assessed. Methods We recruited 50 pubertal adolescents from the oldest cohort of infants born following ICSI. Cross-sectional serum inhibin B levels of all 50 ICSI adolescents, and longitudinal serum inhibin B (assessed at 8 and 14 years) in 25 boys, are reported. Results A statistically significant increase in inhibin B levels was observed between 8 (mean 69 ng/l, SD ± 35) and 14 years (mean 145 ng/l, SD ± 41; P < 0.001). In three quarters of the ICSI boys an increase in serum inhibin B levels of at least 30 between 8 and 14 years was observed. In all but 4 of the 14-year-old ICSI boys serum inhibin B was normal. Serum inhibin B levels in boys from fathers with severe oligozoospermia did not differ from concentrations in boys from fathers without severe oligozoospermia (154 ± 51 and 142 ± 47 ng/l, respectively; P = 0.4). Conclusions The majority of ICSI boys have a significant increase in serum inhibin B, attaining normal values for pubertal status at the age of 14 years. ICSI adolescents from fathers with severely compromised spermatogenesis do not have lower inhibin B levels than those with fathers with normal spermatograms. Further follow-up of the spermatogenic potential of ICSI teenagers up to young adulthood is mandatory to confirm a normal reproductive capacity. © 2010 The Author.


Harper J.C.,University College London | Harper J.C.,Eastman Dental Hospital | Wilton L.,Preimplantation Genetics | Traeger-Synodinos J.,National and Kapodistrian University of Athens | And 8 more authors.
Human Reproduction Update | Year: 2012

Background: Since it was established in 1997, the ESHRE PGD Consortium has been collecting data from international preimplantation genetic diagnosis (PGD) centres. Ten papers have been published, including data from January 1997 to December 2007. Methods: The data collection originally used a hard-copy format, then an excel database and finally a FileMaker Pro database. The indications are divided into five categories: PGD for chromosome abnormalities, sexing for X-linked disease, PGD for single gene defects, preimplantation genetic screening (PGS) and PGD for social sexing. The main end-points are pregnancy outcome and follow-up of deliveries. Results: In data collection I, 16 centres contributed data, which increased to 57 centres by data X (average of 39 centres per data collection). These centres contributed data on over 27 000 cycles that reached oocyte retrieval. Of these cycles, 61% were for aneuploidy screening, 17% for single gene disorders, 16% for chromosomal abnormalities, 4% for sexing of X-linked disease and 2% for social sexing. Cumulatively, 5187 clinical pregnancies gave rise to 4140 deliveries and 5135 newborns (singletons: 3182, twins: 921, triplets: 37). Conclusions: In this paper, we present an overview of the first 10 years of PGD data, highlighting trends. These include the introduction of laser-assisted biopsy, an increase in polar body and trophectoderm biopsy, new strategies, methodologies and technologies for diagnosis, including recently arrays, and the more frequent use of freezing biopsied embryos. The Consortium data reports represent a valuable resource for information about the practice of PGD. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Goossens V.,ESHRE Central Office | Traeger-Synodinos J.,National and Kapodistrian University of Athens | Coonen E.,Maastricht University | De Rycke M.,Center for Medical Genetics | And 4 more authors.
Human Reproduction | Year: 2012

The 11th report of the European Society of Human Reproduction and Embryology Preimplantation Genetic Diagnosis Consortium is presented, documenting cycles collected for the calendar year 2008 and follow-up of the pregnancies and babies born until October 2009 which resulted from these cycles. Since the beginning of the data collections, there has been a steady increase in the number of cycles, pregnancies and babies reported annually. For data collection XI, 53 centres have participated, reporting on 5641 cycles to oocyte retrieval (OR), along with details of the follow-up on 1418 pregnancies and 1169 babies born. A total of 774 OR were reported for chromosomal abnormalities, 96 OR for sexing for X-linked diseases, 1363 OR for monogenic diseases, 3401 OR for preimplantation genetic screening and 5 OR for social sexing. Data XI is compared with the cumulative data for data collections IX. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Moutou C.,University of Strasbourg | Goossens V.,ESHRE Central Office | Coonen E.,Maastricht University | De Rycke M.,Center for Medical Genetics | And 5 more authors.
Human Reproduction | Year: 2014

STUDY QUESTION: How do data in the 12th annual data collection (Data XII) of the European Society of Human Reproduction and Embryology Preimplantation Genetic Diagnosis (PGD) Consortium compare with the cumulative data for collections I-XI? SUMMARY ANSWERS: ince the beginning of the data collections, there has been a steady increase in the number of cycles, pregnancies and babies reported annually.WHAT IS KNOWN ALREADYThe PGD Consortium has collected, analysed and published 11 previous data sets since 1997. STUDY DESIGN, SIZE, DURATION: Data were collected from each participating centre using a pre-designed FileMaker Pro database (versions 5-10). Separate FileMaker Pro files were used for the cycles, pregnancies and baby records. The study documented cycles performed during the calendar year 2009 and follow-up of the pregnancies and babies born which resulted from these cycles (until October 2010). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were submitted by 60 centres (full PGD Consortium members), and the blank files were distributed to each PGD Consortium member centre at the end of 2008. The submitted data were thoroughly analysed to identify incomplete data entries and corrections were requested from the participating centres. Records remaining with incomplete data were excluded from the calculations. Corrections, tables and calculations were made by expert co-authors. MAIN RESULTS AND THE ROLE OF CHANCE: For data collection XII, 60 centres reported data for 6160 cycles with oocyte retrieval (OR), along with details of the follow-up on 1607 pregnancies and 1238 babies born. A total of 870 OR were reported for chromosomal abnormalities, 113 OR for sexing for X-linked diseases, 1597 OR for monogenic diseases, 3551 OR for preimplantation genetic screening and 29 OR for social sexing. LIMITATIONS, REASONS FOR CAUTION: These data cannot include every PGD cycle performed annually, and only indicate the trends in PGD worldwide. WIDER IMPLICATION OF THE FINDINGS: The annual data collections provide an extremely valuable resource for data mining and for following trends in PGD practice. © 2014 The Author.


Belva F.,Center for Medical Genetics | De Schrijver F.,Center for Medical Genetics | Tournaye H.,Center for Reproductive Medicine | Liebaers I.,Center for Medical Genetics | And 4 more authors.
Human Reproduction | Year: 2011

Background: Safety concerns have been expressed regarding the use of immature non-ejaculated spermatozoa for ICSI. Therefore, adverse health outcomes, birth parameters, major anomaly rates and chromosomal aberrations in children born after ICSI using testicular and epididymal sperm were investigated. Methods: Questionnaire data and Results: of physical examinations of 530 children born after ICSI with testicular sperm and of 194 children born after ICSI with epididymal sperm were compared with data on 2516 ICSI children born using ejaculated sperm. Results: Birth parameters, stillborn rates, prematurity rates and rates of low birthweight and very low birthweight were comparable between the non-ejaculated and the ejaculated sperm groups. The perinatal death rate was higher for twins but not for singletons in the non-ejaculated sperm group in comparison to the control cohort of children born using ejaculated sperm. A non-significant increase in major anomalies was reported in the non-ejaculated sperm group in comparison to the ejaculated sperm group. No more anomalies were observed in pre- and post-natal karyotypes from viable pregnancies established using non-ejaculated sperm versus ejaculated sperm.CONCLUSIONOverall neonatal health in terms of birth parameters, major anomalies and chromosomal aberrations in our large cohort of children born by the use of non-ejaculated sperm seems reassuring in comparison to the outcome of children born after the use of ejaculated sperm. © 2011 The Author.


De Brakeleer S.,Vrije Universiteit Brussel | De Greve J.,Vrije Universiteit Brussel | Loris R.,Vrije Universiteit Brussel | Janin N.,CHU de Liege | And 3 more authors.
Human Mutation | Year: 2010

Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported. We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families. ©2010 Wiley-Liss, Inc.


Lavezzi W.A.,Office of the District 5 Medical Examiner | Capacchione J.F.,Uniformed Services University of the Health Sciences | Muldoon S.M.,Uniformed Services University of the Health Sciences | Sambuughin N.,Uniformed Services University of the Health Sciences | And 3 more authors.
Anesthesia and Analgesia | Year: 2013

A healthy 6-year-old boy developed lower extremity rigidity, trismus, and fever after playing in a splash pool. On arrival in the emergency department, he appeared to be seizing. An endotracheal tube was emergently placed using succinylcholine. Cardiac arrest followed. He could not be resuscitated. Postmortem genetic analysis found a novel RYR1 variant. Family testing revealed the same variant in his father who also had muscle contracture testing diagnostic for susceptibility to malignant hyperthermia and central core disease diagnosed histologically. Because there was no exposure to volatile anesthetics before the onset of symptoms, this is a case of "awake" malignant hyperthermia worsened by succinylcholine. Copyright © 2013 International Anesthesia Research Society.


Sequeiros J.,University of Porto | Seneca S.,Center for Medical Genetics | Martindale J.,Sheffield Childrens NHS Foundation Trust
European Journal of Human Genetics | Year: 2010

Many laboratories worldwide are offering molecular genetic testing for spinocerebellar ataxias (SCAs). This is essential for differential diagnosis and adequate genetic counselling. The European Molecular Genetics Quality Network (EMQN) started an SCA external quality assessment scheme in 2004. There was a clear need for updated laboratory guidelines. EMQN and EuroGentest organized a Best Practice (BP) meeting to discuss current practices and achieve consensus. A pre-meeting survey showed that 36 laboratories (20 countries) conducted nearly 18 000 SCA tests the year before, and identified issues to discuss. Draft guidelines were produced immediately after the meeting and discussed online for several months. The final version was endorsed by EMQN, and harmonized with guidelines from other oligonucleotide repeat disorders. We present the procedures taken to organize the survey, BP meeting, as well as drafting and approval of BP guidelines. We emphasize the most important recommendations on (1) pre-test requirements, (2) appropriate methodologies and (3) interpretation and reporting, and focus on the discussion of controversial issues not included in the final document. In addition, after an extensive review of scientific literature, and responding to recommendations made, we now produce information that we hope will facilitate the activities of diagnostic laboratories and foster quality SCA testing. For the main loci, this includes (1) a list of repeat sequences, as originally published; (2) primers in use; and (3) an evidence-based description of the normal and pathogenic repeat-size ranges, including those of reduced penetrance and those in which there is still some uncertainty. This information will be maintained and updated in http://www.scabase.eu. © 2010 Macmillan Publishers Limited All rights reserved.

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