Publications by authors named "Merel van Maarle"

31 Publications

Cytogenetic testing of pregnancy loss tissue: a meta-analysis.

Reprod Biomed Online 2020 Jun 15;40(6):867-879. Epub 2020 Feb 15.

Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam Reproduction and Development Research Institute Amsterdam, the Netherlands. Electronic address:

Many clinics offer routine genetic testing of pregnancy loss tissue. This review presents a comprehensive literature search and meta-analysis on chromosomal abnormality rates of pregnancy loss tissue from women with a single or recurrent pregnancy loss. A total of 55 studies published since 2000 were included, analysed on the prevalence of test failure rates, abnormality detection rates and percentages of trisomy, monosomy X, structural abnormalities and other clinically (ir)relevant abnormalities detected by conventional karyotyping, array-comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) array, fluorescence in-situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA). The detected prevalence of chromosomal abnormalities was 48% (95% confidence interval [CI] 39-57) using aCGH, 38% (95% CI 28-49) with FISH, 25% (95% CI 12-42) using MLPA, 60% (95% CI 58-63) using SNP array and 47% (95% CI 43-51) with conventional karyotyping. The percentage of detected abnormalities did not differ between women that suffered sporadic (46%; 95% CI 39-53) or recurrent (46%; 95% CI 39-52) pregnancy loss. In view of the high prevalence of chromosomal abnormalities in pregnancy loss tissue, and the low chance of recurrence of the same chromosomal aberration, it was concluded that detection of specific chromosomal abnormalities in pregnancy loss tissue has no clinical benefit. Therefore, routine testing of pregnancy loss tissue for chromosomal abnormalities is not recommended.
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http://dx.doi.org/10.1016/j.rbmo.2020.02.001DOI Listing
June 2020

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging.

Prenat Diagn 2020 07 5;40(8):972-983. Epub 2020 May 5.

Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Objective: The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging.

Methods: In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7).

Results: A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases.

Conclusions: These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making.
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http://dx.doi.org/10.1002/pd.5717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497059PMC
July 2020

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

Am J Hum Genet 2019 12 7;105(6):1091-1101. Epub 2019 Nov 7.

Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081HV Amsterdam, the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904791PMC
December 2019

An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality.

Genes Dev 2018 03 19;32(5-6):373-388. Epub 2018 Mar 19.

The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.

It has been well established that histone and DNA modifications are critical to maintaining the equilibrium between pluripotency and differentiation during early embryogenesis. Mutations in key regulators of DNA methylation have shown that the balance between gene regulation and function is critical during neural development in early years of life. However, there have been no identified cases linking epigenetic regulators to aberrant human development and fetal demise. Here, we demonstrate that a homozygous inactivating mutation in the histone deacetylase SIRT6 results in severe congenital anomalies and perinatal lethality in four affected fetuses. In vitro, the amino acid change at Asp63 to a histidine results in virtually complete loss of H3K9 deacetylase and demyristoylase functions. Functionally, SIRT6 D63H mouse embryonic stem cells (mESCs) fail to repress pluripotent gene expression, direct targets of SIRT6, and exhibit an even more severe phenotype than Sirt6-deficient ESCs when differentiated into embryoid bodies (EBs). When terminally differentiated toward cardiomyocyte lineage, D63H mutant mESCs maintain expression of pluripotent genes and fail to form functional cardiomyocyte foci. Last, human induced pluripotent stem cells (iPSCs) derived from D63H homozygous fetuses fail to differentiate into EBs, functional cardiomyocytes, and neural progenitor cells due to a failure to repress pluripotent genes. Altogether, our study described a germline mutation in SIRT6 as a cause for fetal demise, defining SIRT6 as a key factor in human development and identifying the first mutation in a chromatin factor behind a human syndrome of perinatal lethality.
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http://dx.doi.org/10.1101/gad.307330.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900711PMC
March 2018

Mosaic maternal 10qter deletions are associated with FRA10B expansions and may cause false-positive noninvasive prenatal screening results.

Genet Med 2018 11 1;20(11):1472-1476. Epub 2018 Mar 1.

Department of Clinical Genetics, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.

Purpose: Using genome-wide noninvasive prenatal screening (NIPS), we detected a 20-megabase specific deletion starting at 10q25 in eight pregnancies. The deletion could not be confirmed by invasive testing. Since all 10(q25→qter) deletions started close to the FRA10B fragile site in 10q25, we investigated whether the pregnant women were indeed carriers of FRA10B.

Methods: We performed NIPS analysis for all autosomes using single-read sequencing. Analysis was done with the WISECONDOR algorithm. Culture of blood lymphocytes with bromodeoxyuridine was used to detect FRA10B expansions. Fluorescence in situ hybridization and array analysis were used to find maternal and/or fetal deletions.

Results: We confirmed the presence of a FRA10B expansion in all four tested mothers. Fluorescence in situ hybridization and array analysis confirmed the presence of a maternal mosaic deletion of 10(q25→qter).

Conclusion: The recurring 10(q25→qter) deletion detected with NIPS is a false-positive result caused by a maternal low-level mosaic deletion associated with FRA10B expansions. This has important consequences for clinical follow-up, as invasive procedures are unnecessary. Expanded maternal FRA10B repeats should be added to the growing group of variants in the maternal genome that may cause false-positive NIPS results.
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http://dx.doi.org/10.1038/gim.2018.32DOI Listing
November 2018

Preconception carrier screening for multiple disorders: evaluation of a screening offer in a Dutch founder population.

Eur J Hum Genet 2018 02 10;26(2):166-175. Epub 2018 Jan 10.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

Technological developments have enabled carrier screening for multiple disorders. This study evaluated experiences with a preconception carrier screening offer for four recessive disorders in a Dutch founder population. Questionnaires were completed by 182 attendees pretesting and posttesting and by 137 non-attendees. Semistructured interviews were conducted with seven of the eight carrier couples. Attendees were mainly informed about the existence of screening by friends/colleagues (49%) and family members (44%). Familiarity with the genetic disorders was high. Knowledge after counseling increased (p < 0.001); however, still 9%, compared to 29% before counseling, wrongly mentioned an increased risk of having an affected child if both parents are carriers of different disorders. Most attendees (97%) recalled their test results correctly, but two couples reported being carrier of another disorder than reported. Overall, 63% felt worried while waiting for results but anxiety levels returned to normal afterwards. In all, 2/39 (5%) carriers felt less healthy. Screened individuals were very satisfied; they did not regret testing (97%) and would recommend testing to others (97%). The majority (94%) stated that couples should always have a pretest consultation, preferably by a genetic counselor rather than their general practitioner (83%). All carrier couples made reproductive decisions based on their results. Main reason for non-attendance was unawareness of the screening offer. With expanded carrier screening, adequately informing couples pretest and posttesting is of foremost importance. Close influencers (family/friends) can be used to raise awareness of a screening offer. Our findings provide lessons for the implementation of expanded carrier screening panels in other communities and other settings.
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http://dx.doi.org/10.1038/s41431-017-0056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838981PMC
February 2018

Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: results of the TRIDENT study.

Genet Med 2018 04 28;20(5):480-485. Epub 2017 Sep 28.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (
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http://dx.doi.org/10.1038/gim.2017.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929118PMC
April 2018

Women's Experience with Non-Invasive Prenatal Testing and Emotional Well-being and Satisfaction after Test-Results.

J Genet Couns 2017 Dec 30;26(6):1348-1356. Epub 2017 Jun 30.

Department of Clinical Genetics, Section Community Genetics and Amsterdam Public Health Research Institute, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Increasingly, high-risk pregnant women opt for non-invasive prenatal testing (NIPT) instead of invasive diagnostic testing. Since NIPT is less accurate than invasive testing, a normal NIPT result might leave women less reassured. A questionnaire study was performed among pregnant women with elevated risk for fetal aneuploidy based on first-trimester combined test (risk ≥1:200) or medical history, who were offered NIPT in the nationwide Dutch TRIDENT study. Pre- and post-test questionnaires (n = 682) included measures on: experiences with NIPT procedure, feelings of reassurance, anxiety (State-Trait Anxiety Inventory, STAI), child-related anxiety (PRAQ-R), and satisfaction. The majority (96.1%) were glad to have been offered NIPT. Most (68.5%) perceived the waiting time for NIPT results (mean: 15 days, range 5-32) as (much) too long. Most women with a normal NIPT result felt reassured (80.9%) or somewhat reassured (15.7%). Levels of anxiety and child-related anxiety were significantly lower after receiving a normal NIPT result as compared to the moment of intake (p < 0.001). Women with inadequate health literacy or a medical history (e.g. previous child with trisomy) experienced significantly higher post-test-result anxiety (Mean (M) STAI = 31.6 and 30.0, respectively) compared to those with adequate health literacy (M = 28.6) and no medical history (M = 28.6), indicating these women might benefit from extra information and/or guidance when communicating NIPT test-results. Introducing NIPT as an alternative to invasive testing, led to an offer that satisfied and largely reassured high-risk pregnant women.
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http://dx.doi.org/10.1007/s10897-017-0118-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672853PMC
December 2017

With expanded carrier screening, founder populations run the risk of being overlooked.

J Community Genet 2017 Oct 29;8(4):327-333. Epub 2017 May 29.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Genetically isolated populations exist worldwide. Specific genetic disorders, including rare autosomal recessive disorders may have high prevalences in these populations. We searched for Dutch genetically isolated populations and their autosomal recessive founder mutations. We investigated whether these founder mutations are covered in the (preconception) expanded carrier screening tests of five carrier screening providers. Our results show that the great majority of founder mutations are not covered in these screening panels, and these panels may thus not be appropriate for use in founder populations. It is therefore important to be aware of founder mutations in a population when offering carrier tests.
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http://dx.doi.org/10.1007/s12687-017-0309-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614881PMC
October 2017

Oral-facial-digital syndrome type 1 in males: Congenital heart defects are included in its phenotypic spectrum.

Am J Med Genet A 2017 May 3;173(5):1383-1389. Epub 2017 Apr 3.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post-mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left-right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.
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http://dx.doi.org/10.1002/ajmg.a.38179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413846PMC
May 2017

Trial by Dutch laboratories for evaluation of non-invasive prenatal testing. Part II-women's perspectives.

Prenat Diagn 2016 Dec 16;36(12):1091-1098. Epub 2016 Nov 16.

Department of Clinical Genetics, Section Community Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

Objective: To evaluate preferences and decision-making among high-risk pregnant women offered a choice between Non-Invasive Prenatal Testing (NIPT), invasive testing or no further testing.

Methods: 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.

Results: A total of 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. Overall, 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 adequate health literacy (OR = 2.60[1.36-4.95], p = 0.004) were more likely to make an informed choice. Informed choice was associated with less decisional conflict and less anxiety (p < 0.001). Intention to terminate the pregnancy for Down syndrome was higher among women undergoing invasive testing (86.5%) compared to those undergoing NIPT (58.4%) (p < 0.001).

Conclusions: The majority of women had sufficient knowledge and made an informed choice. Continuous attention for counseling is required, especially for low-educated and less health-literate women. © 2016 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.4941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5213994PMC
December 2016

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

JIMD Rep 2017 29;33:87-92. Epub 2016 Sep 29.

Department of Pediatric Neurology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra- and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.
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http://dx.doi.org/10.1007/8904_2016_584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413457PMC
September 2016

Factors for successful implementation of population-based expanded carrier screening: learning from existing initiatives.

Eur J Public Health 2017 04;27(2):372-377

Department of Clinical Genetics, Section of Community Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

Background: Carrier screening for autosomal recessive disorders aims to facilitate reproductive decision-making by identifying couples with a 1-in-4 risk in every pregnancy of having an affected child. Except for a few countries or regions, carrier screening is not widely offered and is mostly ancestry-based. Technological advances enable carrier screening for multiple diseases simultaneously allowing universal screening regardless of ancestry (population-based expanded carrier screening). It is important to study how this can be successfully implemented. This study therefore aims to identify critical factors involved in successful implementation, from a user perspective, by learning from already implemented initiatives.

Methods: Factors associated with successful implementation were identified by: (i) a literature review and (ii) two case studies; studying experiences with carrier screening in two high-risk communities (a Dutch founder population and the Ashkenazi Jewish population), including a survey among community members.

Results: Factors identified were familiarity with (specific) genetic diseases and its availability, high perceived benefits of screening (e.g. screening avoids much suffering), acceptance of reproductive options, perceived risk of being a carrier and low perceived social barriers (e.g. stigmatization). In contrast to the Jewish community, the initial demand for screening in the Dutch founder population did not entirely come from the community itself. However, the large social cohesion of the community facilitated the implementation process.

Conclusion: To ensure successful implementation of population-based expanded carrier screening, efforts should be made to increase knowledge about genetic diseases, create awareness and address personal benefits of screening in a non-directive way.
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http://dx.doi.org/10.1093/eurpub/ckw110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421354PMC
April 2017

Maternal Plasma DNA and RNA Sequencing for Prenatal Testing.

Adv Clin Chem 2016 21;74:63-102. Epub 2016 Jan 21.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

Cell-free DNA (cfDNA) testing has recently become indispensable in diagnostic testing and screening. In the prenatal setting, this type of testing is often called noninvasive prenatal testing (NIPT). With a number of techniques, using either next-generation sequencing or single nucleotide polymorphism-based approaches, fetal cfDNA in maternal plasma can be analyzed to screen for rhesus D genotype, common chromosomal aneuploidies, and increasingly for testing other conditions, including monogenic disorders. With regard to screening for common aneuploidies, challenges arise when implementing NIPT in current prenatal settings. Depending on the method used (targeted or nontargeted), chromosomal anomalies other than trisomy 21, 18, or 13 can be detected, either of fetal or maternal origin, also referred to as unsolicited or incidental findings. For various biological reasons, there is a small chance of having either a false-positive or false-negative NIPT result, or no result, also referred to as a "no-call." Both pre- and posttest counseling for NIPT should include discussing potential discrepancies. Since NIPT remains a screening test, a positive NIPT result should be confirmed by invasive diagnostic testing (either by chorionic villus biopsy or by amniocentesis). As the scope of NIPT is widening, professional guidelines need to discuss the ethics of what to offer and how to offer. In this review, we discuss the current biochemical, clinical, and ethical challenges of cfDNA testing in the prenatal setting and its future perspectives including novel applications that target RNA instead of DNA.
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http://dx.doi.org/10.1016/bs.acc.2015.12.004DOI Listing
August 2016

Changing to NIPT as a first-tier screening test and future perspectives: opinions of health professionals.

Prenat Diagn 2015 Dec 25;35(13):1316-23. Epub 2015 Oct 25.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.

Objective: The aim of this study was to investigate health professionals' opinions toward offering noninvasive prenatal testing (NIPT) as first-tier screening test regardless of pregnant women's risk, and toward a potential broader range of disorders.

Methods: A questionnaire completed by obstetric health professionals (n = 240) after an in-service NIPT training in the West and North of the Netherlands.

Results: The majority (72%) of respondents favored replacing first-trimester combined test (FCT) by NIPT, although 43% preferred to maintain nuchal translucency measurement. Many respondents believed that replacing FCT by NIPT would only have advantages (57%), would lead to more pregnant women opting for prenatal testing (69%), and would simplify counseling (47%). Differences in attitudes toward counseling between health professionals were observed. When considering NIPT to screen for broader range of disorders, the majority (92%) thought that this should include disorders characterized by neonatal death, whereas 52% of the respondents favored testing for fetomaternal risk factors. Overall, 46% thought screening should be offered as a fixed list of disorders.

Conclusion: Most health professionals favor NIPT instead of FCT but prefer to maintain nuchal translucency measurement. If NIPT becomes available as a first-tier screening test, attention remains necessary to ensure that pregnant women make well-informed decisions in line with the aim of prenatal screening.
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http://dx.doi.org/10.1002/pd.4697DOI Listing
December 2015

A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations.

Amyotroph Lateral Scler Frontotemporal Degener 2015 23;16(5-6):410-1. Epub 2015 Jul 23.

a Department of Neurology , The Netherlands.

Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin (OPTN) gene were found in 1% of Japanese patients with sporadic amyotrophic lateral sclerosis (ALS). Autosomal dominantly inherited OPTN mutations have been described as a cause of primary open-angle glaucoma in the Netherlands and were also found in two Dutch sporadic MND patients. We report the first Dutch family with autosomal recessively inherited MND caused by mutations in the OPTN gene.
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http://dx.doi.org/10.3109/21678421.2015.1066821DOI Listing
August 2016

Do people from the Jewish community prefer ancestry-based or pan-ethnic expanded carrier screening?

Eur J Hum Genet 2016 Feb 13;24(2):171-7. Epub 2015 May 13.

Department of Clinical Genetics, Section of Community Genetics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.

Ancestry-based carrier screening in the Ashkenazi Jewish population entails screening for specific autosomal recessive founder mutations, which are rarer among the general population. As it is now technically feasible to screen for many more diseases, the question arises whether this population prefers a limited ancestry-based offer or a pan-ethnic expanded carrier screening panel that goes beyond the diseases that are frequent in their own population, and is offered regardless of ancestry. An online questionnaire was completed by 145 individuals from the Dutch Jewish community (≥ 18 years) between April and July 2014. In total, 64.8% were aware of the existence of ancestry-based carrier screening, and respondents were generally positive about screening. About half (53.8%) preferred pan-ethnic expanded carrier screening, whereas 42.8% preferred ancestry-based screening. Reasons for preferring pan-ethnic screening included 'everyone has a right to be tested', 'fear of stigmatization when offering ancestry-based panels', and 'difficulties with identifying risk owing to mixed backgrounds'. 'Preventing high healthcare costs' was the most important reason against pan-ethnic carrier screening among those in favor of an ancestry-based panel. In conclusion, these findings show that people from the Dutch Jewish community have a positive attitude regarding carrier screening in their community for a wide range of diseases. As costs of expanded carrier screening panels are most likely to drop in the near future, it is expected that these panels will receive more support in the future.
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http://dx.doi.org/10.1038/ejhg.2015.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717216PMC
February 2016

Targeted carrier screening for four recessive disorders: high detection rate within a founder population.

Eur J Med Genet 2015 Mar 30;58(3):123-8. Epub 2015 Jan 30.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

In a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy. The aim of our study was to evaluate the offer of targeted genetic carrier screening as a method to identify high-risk couples for having affected offspring in this high-risk subpopulation. In one year, 203 individuals (92 couples and 19 individuals) were counseled. In total, 65 of 196 (33.2%) tested individuals were carriers of at least one disease, five (7.7%) of them being carriers of two diseases. Carrier frequencies of PCH2, FADS, RCDP1, and OI were 14.3%, 11.2%, 6.1%, and 4.1% respectively. In individuals with a positive family history for one of the diseases, the carrier frequency was 57.8%; for those with a negative family history this was 25.8%. Four PCH2 carrier-couples were identified. Thus, targeted (preconception) carrier screening in this genetically isolated population in which a high prevalence of specific disorders occurs detects a high number of carriers, and is likely to be more effective compared to cascade genetic testing. Our findings and set-up can be seen as a model for carrier screening in other high-risk subpopulations and contributes to the discussion about the way carrier screening can be offered and organized in the general population.
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http://dx.doi.org/10.1016/j.ejmg.2015.01.004DOI Listing
March 2015

A new mutation for Huntington disease following maternal transmission of an intermediate allele.

Eur J Med Genet 2015 Jan 20;58(1):28-30. Epub 2014 Nov 20.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the pathological range (≥ 36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the paternal expansion bias normally observed in HD. A maternal intermediate allele with 33 CAG repeats expanded in transmission to 48 CAG repeats causing a de novo case of HD in the family. Retrospectively, the mother presented with cognitive decline, but HD was never considered in the differential diagnosis. She was diagnosed with dementia and testing for HD was only performed after her daughter had been diagnosed. This observation of an intermediate allele expanding into the full penetrance HD range after maternal transmission has important implications for genetic counselling of females with intermediate repeats.
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http://dx.doi.org/10.1016/j.ejmg.2014.11.005DOI Listing
January 2015

Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder.

Genet Med 2014 Jun 14;16(6):448-59. Epub 2013 Nov 14.

Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Alabama, USA.

Purpose: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1.

Methods: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions.

Results: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions.

Conclusion: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.
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http://dx.doi.org/10.1038/gim.2013.163DOI Listing
June 2014

Complex rearrangement of the exon 6 genomic region among Opitz G/BBB Syndrome MID1 alterations.

Eur J Med Genet 2013 Aug 19;56(8):404-10. Epub 2013 Jun 19.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.

Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by developmental defects of midline structures. The most relevant clinical signs are ocular hypertelorism, hypospadias, cleft lip and palate, laryngo-tracheo-esophageal abnormalities, imperforate anus, and cardiac defects. Developmental delay, intellectual disability and brain abnormalities are also present. The X-linked form of this disorder is caused by mutations in the MID1 gene coding for a member of the tripartite motif family of E3 ubiquitin ligases. Here, we describe 12 novel patients that carry MID1 mutations emphasizing that laryngo-tracheo-esophageal defects are very common in OS patients and, together with hypertelorism and hypospadias, are the most frequent findings among the full spectrum of OS clinical manifestations. Besides missense and nonsense mutations, small insertions and deletions scattered along the entire length of the gene, we found that a consistent number of MID1 alterations are represented by the deletion of single coding exons. Deep characterization of one of these deletions reveals, for the first time within the MID1 gene, a complex rearrangement composed of two deletions, an inversion and a small insertion that may suggest the involvement of concurrent non-homologous mechanisms in the generation of the observed structural variant.
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http://dx.doi.org/10.1016/j.ejmg.2013.05.009DOI Listing
August 2013

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

J Med Genet 2013 May 1;50(5):309-23. Epub 2013 Mar 1.

Molecular Medicine Unit, Birth Defects Research Centre, University College London UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.

Background: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.

Aims And Methods: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.

Results And Conclusions: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.
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http://dx.doi.org/10.1136/jmedgenet-2012-101284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627132PMC
May 2013

Genetics of early miscarriage.

Biochim Biophys Acta 2012 Dec 13;1822(12):1951-9. Epub 2012 Jul 13.

Department of Obstetrics and Gynaecology, University of Amsterdam, The Netherlands.

A miscarriage is the most frequent complication of a pregnancy. Poor chromosome preparations, culture failure, or maternal cell contamination may hamper conventional karyotyping. Techniques such as chromosomal comparative genomic hybridization (chromosomal-CGH), array-comparative genomic hybridization (array-CGH), fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and quantitative fluorescent polymerase chain reaction (QF-PCR) enable us to trace submicroscopic abnormalities. We found the prevalence of chromosome abnormalities in women facing a single sporadic miscarriage to be 45% (95% CI: 38-52; 13 studies, 7012 samples). The prevalence of chromosome abnormalities in women experiencing a subsequent miscarriage after preceding recurrent miscarriage proved to be comparable: 39% (95% CI: 29-50; 6 studies 1359 samples). More chromosome abnormalities are detected by conventional karyotyping compared to FISH or MLPA only (chromosome region specific techniques), and the same amount of abnormalities compared to QF-PCR (chromosome region specific techniques) and chromosomal-CGH and array-CGH (whole genome techniques) only. Molecular techniques could play a role as an additional technique when culture failure or maternal contamination occurs: recent studies show that by using array-CGH, an additional 5% of submicroscopic chromosome variants can be detected. Because of the small sample size as well as the unknown clinical relevance of these molecular aberrations, more and larger studies should be performed of submicroscopic chromosome abnormalities among sporadic miscarriage samples. For recurrent miscarriage samples molecular technique studies are relatively new. It has often been suggested that miscarriages are due to chromosomal abnormalities in more than 50%, but the present review has determined that chromosomal and submicroscopic genetic abnormalities on average are prevalent in maximally half of the miscarriage samples. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.
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http://dx.doi.org/10.1016/j.bbadis.2012.07.001DOI Listing
December 2012

Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis.

Hum Mutat 2012 Aug 22;33(8):1261-6. Epub 2012 May 22.

Departement de Génétique, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France.

Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of β-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism.
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http://dx.doi.org/10.1002/humu.22104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427906PMC
August 2012

[The joys and burdens within clinical genetics--paternal discrepancy causes dilemmas].

Ned Tijdschr Geneeskd 2010 ;154(51-52):A2785

Academisch Medisch Centrum, Amsterdam, afd. Klinische Genetica, the Netherlands.

We present three cases, a 25-year-old woman, a 52-year-old man and a 45-year-old woman, in whom paternal discrepancy (PD) adversely influenced genetic counselling. PD, with an estimated prevalence between 2% and 3%, occurs when a child is identified as being biologically fathered by someone other than the man who believes he is the father. The discovery of PD during genetic testing can cause health problems and psychosocial damage, and can increase costs, as illustrated by our three cases. Opinions vary about whether or not to disclose this sensitive information, and we recommend being as straightforward as possible, while trying to minimize any harm caused. Since genetic techniques that identify PD are improving and increasingly applied, health care providers must be prepared to deal with issues of this nature.
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July 2011

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes.

Eur J Hum Genet 2010 Sep 9;18(9):999-1005. Epub 2010 Jun 9.

Department of Clinical Genetics, School for Oncology & Developmental Biology (GROW), Maastricht UMC, The Netherlands.

Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.
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http://dx.doi.org/10.1038/ejhg.2010.70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987413PMC
September 2010

Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis.

J Med Genet 2010 Mar 20;47(3):169-75. Epub 2009 Oct 20.

Department of Genetics, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Objectives: To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype-phenotype correlations in the X-linked recessive disorder, L1 syndrome.

Methods: DNA from 367 referred patients was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences and for large duplications. Clinical data for 106 patients were collected and used for statistical analysis.

Results: 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p=0.02).

Conclusions: We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.
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http://dx.doi.org/10.1136/jmg.2009.071688DOI Listing
March 2010

Seven lipoprotein lipase gene polymorphisms, lipid fractions, and coronary disease: a HuGE association review and meta-analysis.

Am J Epidemiol 2008 Dec 15;168(11):1233-46. Epub 2008 Oct 15.

United Kingdom HuGENet Coordinating Centre, Strangeways Research Laboratory, Cambridge, United Kingdom.

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism and a major candidate gene for coronary heart disease (CHD). The authors assessed associations between 7 LPL polymorphisms and lipid fractions and CHD risk in population-based cohort, case-control, and cross-sectional studies published by January 2007. Meta-analyses of 22,734 CHD cases and 50,177 controls in 89 association studies focused on the relations of the T-93G (rs1800590), D9N (rs1801177), G188E, N291S (rs268), PvuII (rs285), HindIII (rs320), and S447X (rs328) polymorphisms to high density lipoprotein cholesterol, triglycerides, myocardial infarction, or coronary stenosis. Carriers of 9N or 291S had modestly adverse lipid profiles. Carriers of the less common allele of HindIII or of 447X had modestly advantageous profiles. The combined odds ratio for CHD among carriers was 1.33 (95% confidence interval (CI): 1.14, 1.56) for 9N, 1.07 (95% CI: 0.96, 1.20) for 291S, 0.89 (95% CI: 0.81, 0.98) for the less common HindIII allele, and 0.84 (95% CI: 0.75, 0.94) for 447X. For T-93G (odds ratio (OR) = 1.22, 95% CI: 0.98, 1.52) and PvuII (OR = 0.96, 95% CI: 0.89, 1.04), there were null associations with lipid levels or CHD risk; information on G188E was limited (OR = 2.80, 95% CI: 0.88, 8.87). The study of LPL genotypes confirms the existence of close interrelations between high density lipoprotein cholesterol and triglyceride pathways. The influence of these genotypes on CHD risk warrants further investigation.
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http://dx.doi.org/10.1093/aje/kwn235DOI Listing
December 2008

A new mutation in the SH3BP2 gene showing reduced penetrance in a family affected with cherubism.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 Mar 26;103(3):378-81. Epub 2006 Sep 26.

Department of Oral and Maxillofacial Surgery, Academic Medical Center/Academic Center for Dentistry, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.tripleo.2006.05.012DOI Listing
March 2007

DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma.

Br J Oral Maxillofac Surg 2007 Sep 19;45(6):499-500. Epub 2006 May 19.

Department of Oral and Maxillofacial Surgery, Academic Medical Center/Academic Center for Dentistry (ACTA), University of Amsterdam, The Netherlands.

A mutation of the SH3BP2 gene is known to cause cherubism. As there are clinical and histopathological similarities between central giant cell granuloma and cherubism, we made a constitutional DNA analysis of the SH3BP2 gene in four patients with aggressive giant cell granuloma (having one or more of the following features pain, paraesthesia, rapid growth, or root resorption). We found no mutations in the SH3BP2 gene, which indicates that cherubism is a separate entity. However, a somatic mutation in a specific group of cells could cause the focal lesions in giant cell granuloma. Further DNA analysis of the tissue of giant cell granulomas therefore seems indicated.
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http://dx.doi.org/10.1016/j.bjoms.2006.03.017DOI Listing
September 2007