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Papers by Ron Suijkerbuijk

Journal of Biological Chemistry, 1992

Prenatal Diagnosis, 2020

ObjectiveConventional genetic tests (quantitative fluorescent‐PCR [QF‐PCR] and single nucleotide ... more ObjectiveConventional genetic tests (quantitative fluorescent‐PCR [QF‐PCR] and single nucleotide polymorphism‐array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield.MethodsWe prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first‐degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes.ResultsWe established a genetic rES‐based diagnosis in 8 out of 23 fetuses (35%) without QF‐PCR or ...

Scientific reports, Jan 5, 2016

To properly interpret the result of a pregnant woman's non-invasive prenatal test (NIPT), her... more To properly interpret the result of a pregnant woman's non-invasive prenatal test (NIPT), her a priori risk must be taken into account in order to obtain her personalised a posteriori risk (PPR), which more accurately expresses her true likelihood of carrying a foetus with trisomy. Our aim was to develop a tool for laboratories and clinicians to calculate easily the PPR for genome-wide NIPT results, using diploid samples as a control group. The tool takes the a priori risk and Z-score into account. Foetal DNA percentage and coefficient of variation can be given default settings, but actual values should be used if known. We tested the tool on 209 samples from pregnant women undergoing NIPT. For Z-scores < 5, the PPR is considerably higher at a high a priori risk than at a low a priori risk, for NIPT results with the same Z-score, foetal DNA percentage and coefficient of variation. However, the PPR is effectively independent under all conditions for Z-scores above 6. A high PP...

Prenatal diagnosis, Jan 14, 2016

To evaluate preferences and decision-making amongst high-risk pregnant women offered a choice bet... more To evaluate preferences and decision-making amongst high-risk pregnant women offered a choice between Non-Invasive Prenatal Testing (NIPT), invasive testing or no further testing. Nationwide implementation study (TRIDENT) offering NIPT as contingent screening test for women at increased risk for fetal aneuploidy based on first-trimester combined testing (>1:200) or medical history. A questionnaire was completed after counseling assessing knowledge, attitudes and participation following the Multidimensional Measure of Informed Choice. 1091/1253 (87%) women completed the questionnaire. Of these, 1053 (96.5%) underwent NIPT, 37 (3.4%) invasive testing and 1 (0.1%) declined testing. 91.7% preferred NIPT because of test safety. 77.9% made an informed choice, 89.8% had sufficient knowledge and 90.5% had positive attitudes towards NIPT. Women with intermediate (Odds Ratio(OR) = 3.51[1.70-7.22],p < 0.001) or high educational level (OR = 4.36[2.22-8.54],p < 0.001) and women with ade...

American journal of human genetics, 1991

The recently developed competitive in situ hybridization (CISH) strategy was applied to the analy... more The recently developed competitive in situ hybridization (CISH) strategy was applied to the analysis of chromosome 12 aberrations in testicular germ cell tumors (TGCTs). DNAs from two rodent-human somatic cell hybrids, containing either a normal chromosome 12 or the p arm of chromosome 12 as their unique human material, were used as probes. Our results demonstrate a genuine iso-12p character of the standard marker chromosome in TGCTs. Moreover, variant markers were identified representing translocation products that also involve chromosome 12.

Cancer research, Jan 15, 1994

We report the chromosomal characteristics of a recurrent pineal non-seminomatous germ cell tumor ... more We report the chromosomal characteristics of a recurrent pineal non-seminomatous germ cell tumor in a 16-year-old male patient. This non-seminomatous tumor had the following components: embryonal carcinoma, teratoma, yolk sac tumor, and trophoblastic giant cells. Chromosome analysis showed a near-triploid karyotype (64 chromosomes), including two copies of an isochromosome 12p. This latter finding could be confirmed using 12p-specific competitive in situ hybridization techniques applied to cultured cells (T2219-P6 cell line) derived from the tumor. The present findings are in keeping with the hypothesis that isochromosome 12p formation is associated with the development of malignant extragonadal germ cell tumors.

Prenatal Diagnosis, 2006

To investigate the effect of factors involved in cell culturing and slide preparation of amniotic... more To investigate the effect of factors involved in cell culturing and slide preparation of amniotic fluid (AF) and chorionic villus biopsies (CVB) for prenatal cytogenetic diagnosis. The effect on the outcome of our standard AF cell culture procedure of volume and appearance of the submitted AF specimen, gynaecologist performing the amniocentesis, week of gestation in which the specimen was taken and culture medium was retrospectively investigated. In a prospective study controlled experimental variation was introduced in composition of fixative, relative humidity, temperature and airflow during slide preparation from primary CVB and AF in situ cultures. For evaluation, analysis of regression or variance was used. Provided that at least 0.8 mL AF per culture dish was admitted, none of the investigated factors appeared as critical resulting in unacceptable variation in outcome. Variation in appearance of the AF had a relatively major impact: bloody or brown AF resulted in a 3 days longer culture time. To a limited degree, metaphase quality of AF and CVB cells was affected by composition of fixative, relative humidity, ambient temperature and airflow during slide preparation. Current prenatal cytogenetic practice as described here appears in general to be robust and reliable. The investigated conditions are not critical within the investigated range. Expensive measures for fine control of these conditions are, therefore, not required.

The Journal of Urology, 1996

Purpose: We reviewed available cytogenetic and m olecular findings in testicu lar germ cell tum o... more Purpose: We reviewed available cytogenetic and m olecular findings in testicu lar germ cell tum ors, and th e ir possible application to clinical, pathological an d basic p aram eters. M aterials and Methods: Findings in th e lite ra tu re on te stic u la r germ cell tum ors as w ell as those from our laboratory were sum m arized, including a listin g of th e cytogenetic findings on testicu lar germ cell tum ors to date w ith some illu stratio n s, Results: Testicular germ cell tum ors are characterized in m ost cases by the presence of an i(12p) isochromosome. In tum ors w ithout such an abnorm al chrom osom e studies u sin g fluores cence in situ hybridization and m olecular approaches have d em o n strated eith er m asking of th e i(12p) or th e presence of extra 12p sequences in the karyotype. A lthough testicu lar germ cell tum ors are often associated w ith chromosome changes in addition to th e i(12p), no o th er specifically recu rren t stru ctu ral chromosome changes have b e e n found. B ased on th e cytogenetic and m olecular findings in testicular germ cell tum ors, a hy p o th etical schem e for th e genetic events leading to these tum ors is presented. Conclusions: The genetic events leading to genesis of te stic u la r germ cell tum ors in m en a p p ea r to be related to aneuploidization followed by th e form ation of a n i(12p) isochrom osome, th e la tte r characterizing the preponderant num ber of te stic u la r germ cell tum ors. The exact role of th e i(12p) isochromosome in testicular germ cell tum or p ath o g en esis rem ain s to be determ ined, as is tru e of the genes involved in or affected by these tum ors. B ased on p re se n tly available in fo rm a tion, a hypothetical pathogenetic and oncogenetic model for th e developm ent of te stic u la r germ cell tum ors is presented.

Journal of Medical Genetics, 1992

Human Molecular Genetics, 1996

In several families with non-specific X-linked mental retardation (XLMR) linkage analyses have as... more In several families with non-specific X-linked mental retardation (XLMR) linkage analyses have assigned the underlying gene defect to the pericentromeric region of the X chromosome, but none of these genes have been isolated so far. Here, we report on the cloning and characterization of a novel gene, DXS6673E, that maps to Xq13.1, is subject to X-inactivation and is disrupted in the 5′ untranslated region by a balanced X;13 translocation in a mentally retarded female. The DXS6673E gene is highly conserved among vertebrates and its expression is most abundant in brain. It encodes a hydrophilic protein of 1358 amino acids (aa) that does not show sequence homology to other known proteins. A segment of this protein consisting of neutral and hydrophobic aa with a proline residue in every second position may represent a transmembrane domain. Almost complete sequence identity was found between the 3′ end of the DXS6673E gene and two expressed sequence tags (ESTs) and between the 5′ end of the DXS6673E gene and a third EST. Moreover, weaker sequence similarity was observed between coding regions and two other ESTs.

Human Molecular Genetics, 1994

Genomics, 1992

General introduction 1.1 Chromosomal aberrations in human cancer 1.2 Scope of the thesis 15 Refer... more General introduction 1.1 Chromosomal aberrations in human cancer 1.2 Scope of the thesis 15 References 2. Fluorescence in situ hybridization techniques 2.1 Introduction 2.2 Fluorescent in situ identification of human marker chromosomes using flow sorting and Alu element-mediated PCR 2.3 Generation of a panel of somatic cell hybrids containing fragments of human chromosome 12p by X-ray irradiation and cell fusion References 3. Analysis of chromosome 12 aberrations in human germ cell tumors 59

Genes, Chromosomes and Cancer, 2002

In this investigation, we selected PAX3/FKHR and PAX7/FKHR fusion transcript-positive and -negati... more In this investigation, we selected PAX3/FKHR and PAX7/FKHR fusion transcript-positive and -negative alveolar rhabdomyosarcomas (ARMSs) and embryonal rhabdomyosarcomas (ERMSs) with and without anaplastic features, to ascertain genomic imbalance differences and/or similarities within these histopathologic and genetic rhabdomyosarcoma (RMS) variants. Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies were performed on 45 rhabdomyosarcoma specimens consisting of 23 ARMSs and 22 ERMSs (12 ERMS cases were included from an earlier study). The anaplastic variant of RMS has not previously been subjected to CGH analysis. Overall, the most prominent imbalances were gain of chromosomes or chromosomal regions 2/2q (40%), 7/7q (31%), 8/8p (53%), 11/11q (31%), 12q13-15 (49%), 13q14 (22%), and 20/20p (31%), and loss of 1p36 (27%), 3p14-21 (22%), 9q21-22 (33%), 10q22-qter (18%), 16q (27%), 17p (22%), and 22 (22%). These gains and losses were distributed equally between ARMS and ERMS histologic subtypes (excluding 7/7q and 11/11q gain that were observed chiefly in ERMS), demonstrating that these entities are similar with respect to recurrent genomic imbalances. Moreover, genomic imbalances were also evenly distributed among the ARMS fusion transcript subtypes, providing evidence for a genetic kinship despite the absence of a fusion transcript in some cases. Genomic amplification was detected in 26% and 23% of the ARMS and ERMS cases, respectively (with nearly all of the latter subset exhibiting anaplastic features). One amplicon, involving 15q25-26, corresponds to the locus of the insulin-like growth factor type I receptor (IGF1R) gene. Amplification of IGF1R was confirmed molecularly in the cases exhibiting a 15q25-26 amplicon. In summary, these results indicate that genomic gains and losses involve alike chromosomes with similar frequencies within the histopathologic and genetic subtypes of rhabdomyosarcoma, that genomic amplification is frequent not only in the alveolar histologic subtype of rhabdomyosarcoma but also in ERMS with anaplasia, and that amplification of IGF1R possibly plays a role in the development or progression of a subset of rhabdomyosarcomas.

Genes, Chromosomes and Cancer, 1997

Comparative genomic hybridization analysis of a primary osteosarcoma and its metastasis revealed ... more Comparative genomic hybridization analysis of a primary osteosarcoma and its metastasis revealed two regions of D N A amplification, one at I7pl 1.2-12 and one at !9 q I2-l3. Subsequent representational difference analysis of the primary tumor resulted in the isolation of two distinct tumor-amplified D N A fragments originating from chromosome 19. A YAC clone corresponding to one of the two isolated D N A fragments was used for fluorescence in situ hybridization on normai human lymphocyte metaphases and tumor-derived nuclei. This resulted in the localization of this YAC to 19q 12-13-1 and confirmed the amplification status of the isolated fragment in the tumors. The availability of such RDA-isolated sequences may be instrumental in the search for genes relevant for tumor development.

Clinical Chemistry, 2013

BACKGROUND Noninvasive trisomy 21 detection performed by use of massively parallel sequencing is ... more BACKGROUND Noninvasive trisomy 21 detection performed by use of massively parallel sequencing is achievable with high diagnostic sensitivity and low false-positive rates. Detection of fetal trisomy 18 and 13 has been reported as well but seems to be less accurate with the use of this approach. The reduced accuracy can be explained by PCR-introduced guanine-cytosine (GC) bias influencing sequencing data. Previously, we demonstrated that sequence data generated by single molecule sequencing show virtually no GC bias and result in a more pronounced noninvasive detection of fetal trisomy 21. In this study, single molecule sequencing was used for noninvasive detection of trisomy 18 and 13. METHODS Single molecule sequencing was performed on the Helicos platform with free DNA isolated from maternal plasma from 11 weeks of gestation onward (n = 17). Relative sequence tag density ratios were calculated against male control plasma samples and results were compared to those of previous karyot...

Cancer Genetics and Cytogenetics, 1994

The molecular characterization of o recurring complex chromosomal translocation involv-•ng 6p21, ... more The molecular characterization of o recurring complex chromosomal translocation involv-•ng 6p21, 6p22, 6q23, and 11q13 in two independent but similar extragonadal human germ cell tumors was initiated using fluorescence in situ hybridization (FISH) and pulse field gel electrophoresis (PFGE) techniques. By using a series of specific probes from the 11q13 region, the translocation breakpoint in this chromosomal band could be located within a long-range restriction enzyme map in between the markers DllS457 and DllS546. ]~n addition, aberrantly hybridizing restriction fragments were revealed by PFGF, in bath tumors, indicating that the breakpoint region must be located within a distance of at maximum 200 kilobase pairs (kbp) from the nearest DNA marker (DllS546).

Cancer Genetics and Cytogenetics, 1996

Comparative genomic hybridization (CGH) was carried out on 15 primary testicular germ cell tumors... more Comparative genomic hybridization (CGH) was carried out on 15 primary testicular germ cell tumors (TGCT) o f adolescents and adults and two metastatic residual tumors after chemotherapeu tic treatment. The results were compared with karyotypic data obtained form the same tum or specimens after direct harvesting o f metaphases or short-term in vitro culture. .Both techniques revealed that the m ost consistent abnormality in prim ary TGCT is gain o f 12p-sequences. Although In m o st cases over representation o f the complete short arm was observed, CGH revealed a specific amplification of 1 2 p ll.l-p l2 ,l region in two independent primary tumors. In additiont loss of (parts of) chromosome 13 (always involving q31-qter), and gain o f (parts of) chromosome 7 (mostly involving q ll), (parts of) chro mosome 8, and the X chromosome were detected in more than 25% o f the tumors by this latter tech nique. Loss of 6ql5-q21 in both residual tumors analyzed m a y suggest a role for this anomaly in acquired resistance to chemotherapeutic treatm ent Overall, the CGH analyses confirmed gains and losses o f certain chromosomal regions in TGCT as observed by karyotyping, and thus support their role in the development o f these neoplasm s. The ampli fication o f a restricted region o f 12p in prim ary TGCT confirms and extends our previous observations and, as such, represents an im portant step forward in the identification o f gene(s) on 12p relevant for the pathogenesis o f these tumors.