Publications by authors named "Jacques C Giltay"

26 Publications

  • Page 1 of 1

Maternal risk associated with the VACTERL association: A case-control study.

Birth Defects Res 2020 11 22;112(18):1495-1504. Epub 2020 Jul 22.

Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center (Radboudumc), Nijmegen, the Netherlands.

Background: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors.

Methods: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI).

Results: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL.

Conclusion: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.
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http://dx.doi.org/10.1002/bdr2.1773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689936PMC
November 2020

A de novo variant in the human HIST1H4J gene causes a syndrome analogous to the HIST1H4C-associated neurodevelopmental disorder.

Eur J Hum Genet 2020 05 5;28(5):674-678. Epub 2019 Dec 5.

Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.

We report here a de novo missense variant in HIST1H4J resulting in a complex syndrome combining growth delay, microcephaly and intellectual disability. Trio whole exome sequencing (WES) revealed that the proband was heterozygous for a de novo c.274 A > G p.(K91E) variant in HIST1H4J, a gene not yet associated with human disease. The patient presented with profound intellectual disability, microcephaly, and dysmorphic facial features. Functional consequences of the identified de novo missense variant were evaluated in zebrafish embryos, where they affected general development, especially resulting in defective head organs and reduced body axis length. Our results show that the monoallelic p.K91E substitution on HIST1H4J underlies a human syndrome that is genetically and phenotypically akin to the HIST1H4C-associated neurodevelopmental disorder resulting from p.K91A and p.K91Q substitions in HIST1H4C. The highly overlapping patient phenotypes highlight functional similarities between HIST1H4J and HIST1H4C perturbations, establishing the singular importance of K91 across histone H4 genes for vertebrate development.
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http://dx.doi.org/10.1038/s41431-019-0552-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171094PMC
May 2020

Phenotype delineation of ZNF462 related syndrome.

Am J Med Genet A 2019 10 30;179(10):2075-2082. Epub 2019 Jul 30.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.
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http://dx.doi.org/10.1002/ajmg.a.61306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935050PMC
October 2019

Extreme phenotypic variability of a novel GLI2 mutation in a large family with panhypopituitarism and polydactyly: clinical implications.

Clin Endocrinol (Oxf) 2018 09 3;89(3):378-380. Epub 2018 Jul 3.

Department of Clinical Genetics, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.

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http://dx.doi.org/10.1111/cen.13760DOI Listing
September 2018

Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue.

Hum Mol Genet 2017 12;26(23):4689-4698

Department of Molecular Genetics, Cancer Genomics Netherlands, Erasmus MC, Rotterdam, The Netherlands.

The rare recessive developmental disorder Trichothiodystrophy (TTD) is characterized by brittle hair and nails. Patients also present a variable set of poorly explained additional clinical features, including ichthyosis, impaired intelligence, developmental delay and anemia. About half of TTD patients are photosensitive due to inherited defects in the DNA repair and transcription factor II H (TFIIH). The pathophysiological contributions of unrepaired DNA lesions and impaired transcription have not been dissected yet. Here, we functionally characterize the consequence of a homozygous missense mutation in the general transcription factor II E, subunit 2 (GTF2E2/TFIIEβ) of two unrelated non-photosensitive TTD (NPS-TTD) families. We demonstrate that mutant TFIIEβ strongly reduces the total amount of the entire TFIIE complex, with a remarkable temperature-sensitive transcription defect, which strikingly correlates with the phenotypic aggravation of key clinical symptoms after episodes of high fever. We performed induced pluripotent stem (iPS) cell reprogramming of patient fibroblasts followed by in vitro erythroid differentiation to translate the intriguing molecular defect to phenotypic expression in relevant tissue, to disclose the molecular basis for some specific TTD features. We observed a clear hematopoietic defect during late-stage differentiation associated with hemoglobin subunit imbalance. These new findings of a DNA repair-independent transcription defect and tissue-specific malfunctioning provide novel mechanistic insight into the etiology of TTD.
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http://dx.doi.org/10.1093/hmg/ddx351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886110PMC
December 2017

Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control.

Nat Genet 2017 Nov 18;49(11):1642-1646. Epub 2017 Sep 18.

Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.

Covalent modifications of histones have an established role as chromatin effectors, as they control processes such as DNA replication and transcription, and repair or regulate nucleosomal structure. Loss of modifications on histone N tails, whether due to mutations in genes belonging to histone-modifying complexes or mutations directly affecting the histone tails, causes developmental disorders or has a role in tumorigenesis. More recently, modifications affecting the globular histone core have been uncovered as being crucial for DNA repair, pluripotency and oncogenesis. Here we report monoallelic missense mutations affecting lysine 91 in the histone H4 core (H4K91) in three individuals with a syndrome of growth delay, microcephaly and intellectual disability. Expression of the histone H4 mutants in zebrafish embryos recapitulates the developmental anomalies seen in the patients. We show that the histone H4 alterations cause genomic instability, resulting in increased apoptosis and cell cycle progression anomalies during early development. Mechanistically, our findings indicate an important role for the ubiquitination of H4K91 in genomic stability during embryonic development.
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http://dx.doi.org/10.1038/ng.3956DOI Listing
November 2017

Mutations in -acetylglucosamine (-GlcNAc) transferase in patients with X-linked intellectual disability.

J Biol Chem 2017 07 5;292(30):12621-12631. Epub 2017 Jun 5.

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. Electronic address:

-Acetylglucosamine (-GlcNAc) transferase (OGT) regulates protein -GlcNAcylation, an essential and dynamic post-translational modification. The -GlcNAc modification is present on numerous nuclear and cytosolic proteins and has been implicated in essential cellular functions such as signaling and gene expression. Accordingly, altered levels of protein -GlcNAcylation have been associated with developmental defects and neurodegeneration. However, mutations in the gene have not yet been functionally confirmed in humans. Here, we report on two hemizygous mutations in in individuals with X-linked intellectual disability (XLID) and dysmorphic features: one missense mutation (p.Arg284Pro) and one mutation leading to a splicing defect (c.463-6T>G). Both mutations reside in the tetratricopeptide repeats of OGT that are essential for substrate recognition. We observed slightly reduced levels of OGT protein and reduced levels of its opposing enzyme -GlcNAcase in both patient-derived fibroblasts, but global -GlcNAc levels appeared to be unaffected. Our data suggest that mutant cells attempt to maintain global -GlcNAcylation by down-regulating -GlcNAcase expression. We also found that the c.463-6T>G mutation leads to aberrant mRNA splicing, but no stable truncated protein was detected in the corresponding patient-derived fibroblasts. Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding and exhibited reduced glycosylation activity against a complex array of glycosylation substrates and proteolytic processing of the transcription factor host cell factor 1, which is also encoded by an XLID-associated gene. We conclude that defects in -GlcNAc homeostasis and host cell factor 1 proteolysis may play roles in mediation of XLID in individuals with mutations.
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http://dx.doi.org/10.1074/jbc.M117.790097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535036PMC
July 2017

Tetraploid/Diploid Mosaicism in Cultured Genital Skin Fibroblasts: Is It Causally Related to Penoscrotal Hypospadias?

Mol Syndromol 2016 Jul 2;7(3):153-9. Epub 2016 Jun 2.

Departments of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Tetraploid/diploid mosaicism is a rare chromosomal abnormality that is infrequently reported in patients with severe developmental delay, growth retardation, and short life span. Here, we present a 6-year-old patient with severe penoscrotal hypospadias and a coloboma of the left eye but with normal growth, normal psychomotor development, and without dysmorphisms. We considered a local, mosaic sex chromosomal aneuploidy as a possible cause of his genital anomaly and performed karyotyping in cultured fibroblasts from the genital skin, obtained during surgical correction. Tetraploid/diploid (92,XXYY/46,XY) mosaicism was found in 43/57 and 6/26 metaphases in 2 separate cultures, respectively. Buccal smear cells, blood lymphocytes, and cells from urine sediment all showed diploidy. We investigated whether this chromosomal abnormality could be found in other patients with severe hypospadias and karyotyped genital fibroblasts of 6 additional patients but found only low frequencies (<11%) of tetraploid cells, not statistically different from those found in control males with no hypospadias. This is the first time tetraploid mosaicism is found in such a high percentage in a patient without psychomotor retardation, dysmorphisms or growth delay. Although the relationship between this observed mosaicism in cultured cells and the underlying pathogenetic mechanism in penoscrotal hypospadias remains to be determined, our data clearly illustrate the power of cytogenetic techniques in detecting mosaicism compared to next-generation sequencing techniques, in which DNA pooled from multiple cells is used.
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http://dx.doi.org/10.1159/000446203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988250PMC
July 2016

Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations.

Rheumatology (Oxford) 2016 May 10;55(5):902-10. Epub 2016 Feb 10.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht.

Objective: To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms.

Results: Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved.

Conclusion: This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.
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http://dx.doi.org/10.1093/rheumatology/kev439DOI Listing
May 2016

Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.

Kidney Int 2016 Feb;89(2):476-86

The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5–15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.
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http://dx.doi.org/10.1038/ki.2015.319DOI Listing
February 2016

[An infant with remarkable soles of his feet].

Ned Tijdschr Geneeskd 2015 ;160:A9500

Beatrixziekenhuis, afd. Kindergeneeskunde, Gorinchem.

We describe a 4-month-old male infant with a ridge across the soles of both feet without clinical signs of illness. The abnormality was diagnosed as a precalcaneal congenital fibrolipomatous hamartoma.
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November 2017

Further confirmation of the MED13L haploinsufficiency syndrome.

Eur J Hum Genet 2015 Jan 30;23(1):135-8. Epub 2014 Apr 30.

Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.

MED13L haploinsufficiency syndrome has been described in two patients and is characterized by moderate intellectual disability (ID), conotruncal heart defects, facial abnormalities and hypotonia. Missense mutations in MED13L are linked to transposition of the great arteries and non-syndromal intellectual disability. Here we describe two novel patients with de novo MED13L aberrations. The first patient has a de novo mutation in the splice acceptor site of exon 5 of MED13L. cDNA analysis showed this mutation results in an in-frame deletion, removing 15 amino acids in middle of the conserved MED13L N-terminal domain. The second patient carries a de novo deletion of exons 6-20 of MED13L. Both patients show features of the MED13L haploinsufficiency syndrome, except for the heart defects, thus further confirming the existence of the MED13L haploinsufficiency syndrome.
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http://dx.doi.org/10.1038/ejhg.2014.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266749PMC
January 2015

The genetic basis of DOORS syndrome: an exome-sequencing study.

Lancet Neurol 2014 Jan 29;13(1):44-58. Epub 2013 Nov 29.

Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.

Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

Findings: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

Interpretation: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

Funding: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.
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http://dx.doi.org/10.1016/S1474-4422(13)70265-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895324PMC
January 2014

Genes in the ureteric budding pathway: association study on vesico-ureteral reflux patients.

PLoS One 2012 27;7(4):e31327. Epub 2012 Apr 27.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p<0.005 were included in a follow-up study in 202 cases and 892 controls. Of the total cohort, ~50% showed a clear-cut primary VUR phenotype and ~25% had both a duplex collecting system and VUR. We also looked for association in these two extreme phenotype groups. None of the SNPs reached a significant p-value. Common genetic variants in four genes (GREM1, EYA1, ROBO2 and UPK3A) show a trend towards association with the development of primary VUR (GREM1, EYA1, ROBO2) or duplex collecting system (EYA1 and UPK3A). SNPs in three genes (TGFB1, GNB3 and VEGFA) have been shown to be associated with VUR in other populations. Only the result of rs1800469 in TGFB1 hinted at association in our study. This is the first extensive study of common variants in the genes of the ureteric budding pathway and the genetic susceptibility to primary VUR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338743PMC
September 2012

Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI).

Fertil Steril 2012 Jan 17;97(1):141-6.e2. Epub 2011 Nov 17.

Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: To evaluate the significance of NR5A1 mutations in a large, well-phenotyped cohort of women with primary ovarian insufficiency (POI). Mutations in the NR5A1 gene (SF-1) were previously described in disorders of sexual development and adrenal insufficiency. Recently, a high frequency of NR5A1 gene mutations was reported in a small group of women with POI.

Design: Cross-sectional cohort study.

Setting: University hospital.

Patient(s): Well-phenotyped women (n = 386) with secondary amenorrhea and diagnosed with POI, including women with familial POI (n = 77).

Intervention(s): None.

Main Outcome Measure(s): The entire coding region and splice sites of the NR5A1 gene were PCR-amplified and sequenced. The pathogenicity of identified mutations was predicted in silico by assessing Align-GVGD class and Grantham score.

Result(s): Sequencing was successful in 356 patients with POI. In total, 9 mutations were identified in 10 patients. Five of these mutations concerned novel nonconservative mutations occurring in 5 patients. Prediction of effect on protein function showed low to intermediate pathogenicity for all nonconservative mutations. The overall NR5A1 gene mutation rate was 1.4%.

Conclusion(s): The current study demonstrates that mutations in the NR5A1 gene are rare in women with POI. Primary ovarian insufficiency remains unexplained in the great majority of patients; therefore, continued efforts are needed to elucidate its underlying genetic factors.
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http://dx.doi.org/10.1016/j.fertnstert.2011.10.032DOI Listing
January 2012

Is joint hypermobility associated with vesico-ureteral reflux? An assessment of 50 patients.

BJU Int 2012 Apr 24;109(8):1243-8. Epub 2011 Aug 24.

Departments of Medical Genetics, University Medical Centre Utrecht, The Netherlands.

Objective: To assess whether there is an increased prevalence of joint hypermobility in patients with vesico-ureteric reflux (VUR).

Materials And Methods: We studied 50 patients with primary VUR and matched controls drawn from a reference population. Joint mobility was assessed using the Bulbena hypermobility score.

Results: We identified significantly more patients with VUR with generalized joint hypermobility than controls (24% vs 6.7%, P= 0.007).

Conclusion: Our findings confirm our clinical observation of an increased rate of joint hypermobility in patients with VUR. We speculate that an altered composition of the connective tissue may contribute to the severity of the (pre-existing) VUR phenotype.
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http://dx.doi.org/10.1111/j.1464-410X.2011.10469.xDOI Listing
April 2012

Attitudes of Klinefelter men and their relatives towards TESE-ICSI.

J Assist Reprod Genet 2011 Sep 30;28(9):809-14. Epub 2011 Jun 30.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: At the start of the implementation of TESE-ICSI for Klinefelter men in the Netherlands, we aimed to evaluate their wish to father children and their attitudes towards this artificial reproduction technique.

Methods: Questionnaires were distributed to members of the Dutch Klinefelter Association (n = 365) and to Klinefelter cases known at our Department (n = 58). Questions addressed several aspects: socio-demographic characteristics, ascertainment of diagnosis, children and child wish, and TESE-ICSI. Data were characterized using descriptive statistics.

Results: A total of 260 questionnaires (corresponding to 194 cases, 46%) were returned. A possible wish to father children was reported by 90% of Klinefelter men. 70% of Klinefelter men and 74% of their partners would (probably) opt for TESE-ICSI.

Conclusion: The majority of Dutch Klinefelter men and their partners desire to have children and have a positive attitude towards TESE-ICSI. Concerns include the risk of congenital malformations/developmental delay of the child and the limited success rate of TESE-ICSI.
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http://dx.doi.org/10.1007/s10815-011-9603-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169690PMC
September 2011

The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family.

Hum Mutat 2010 Dec;31(12):E1915-27

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

Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation.
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http://dx.doi.org/10.1002/humu.21372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051827PMC
December 2010

Klinefelter syndrome: clinical and molecular aspects.

Expert Rev Mol Diagn 2010 Sep;10(6):765-76

University Medical Centre Utrecht, Department of Medical Genetics, Utrecht, The Netherlands.

Klinefelter syndrome is the most common chromosome abnormality in humans. The estimated prevalence is one in 500 to one in 1000 males but due to the widely variable and often aspecific features, only one in four cases are recognized. The most specific clinical features which can be observed at adult age are small testes, gynecomastia, female distribution of fat and body hair, slightly increased body length due to an increased leg length and azoospermia. Cognition is characterized by verbal deficits and psychosocial features include autistiform behavior. Structural brain abnormalities have been observed by MRI, such as decreased brain volumes and a decrease of asymmetry in areas corresponding to language performance. In the vast majority of cases a non-mosaic 47,XXY karyotype is observed. Parental imprinting of the extra X chromosome, variable inactivation of some X-chromosomal genes and CAG repeat length polymorphism of the androgen receptor may all be related to the variability of the phenotype. Surgical procedures of obtaining sperm in combination with repeated intracytoplasmic sperm injection/in vitro fertilization treatment may allow up to one in four men with Klinefelter syndrome to father children.
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http://dx.doi.org/10.1586/erm.10.63DOI Listing
September 2010

[Diagnostic images (417) A girl with a 'tail' Lumbosacral hypertrichosis (faun tail)].

Ned Tijdschr Geneeskd 2009 May;153(18):884

Universitair Medisch Centrum Utrecht.

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May 2009

Linkage study of 14 candidate genes and loci in four large Dutch families with vesico-ureteral reflux.

Pediatr Nephrol 2007 Aug 12;22(8):1129-33. Epub 2007 May 12.

Department of Medical Genetics KC.04.084.2, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands.

Vesico-ureteral reflux (VUR) is a major contributing factor to end-stage renal disease in paediatric patients. Primary VUR is a familial disorder, but little is known about its genetic causes. To investigate the involvement of 12 functional candidate genes and two reported loci in VUR, we performed a linkage study in four large, Dutch, multi-generational families with multiple affected individuals. We were unable to detect linkage to any of the genes and loci and could exclude the GDNF, RET, SLIT2, SPRY1, PAX2, AGTR2, UPK1A and UPK3A genes and the 1p13 and 20p13 loci from linkage to VUR. Our results provide further evidence that there appears to be genetic heterogeneity in VUR.
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http://dx.doi.org/10.1007/s00467-007-0492-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1915619PMC
August 2007

Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample.

Schizophr Res 2007 Jul 24;93(1-3):399-402. Epub 2007 Apr 24.

Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, Utrecht, The Netherlands.

The presence of an additional X-chromosome in Klinefelter patients provides an opportunity to study the influence of this chromosome on psychiatric disorders. Previous studies have reported an excess of Klinefelter patients in psychiatric patient groups. We report an increased prevalence of psychiatric disorders including psychotic disorders in a sample of Klinefelter patients but could not find evidence of an effect of the parental origin of the extra X-chromosome on the psychiatric phenotype. Nevertheless, these findings provide further support for the role of the X-chromosome in the susceptibility to psychiatric disorders in general and psychotic disorders in particular.
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http://dx.doi.org/10.1016/j.schres.2007.03.015DOI Listing
July 2007

Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux.

Am J Hum Genet 2007 Apr 14;80(4):616-32. Epub 2007 Feb 14.

Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.
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http://dx.doi.org/10.1086/512735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852714PMC
April 2007

Apparent primary follicle-stimulating hormone deficiency is a rare cause of treatable male infertility.

Fertil Steril 2004 Mar;81(3):693-6

Department of Biomedical Genetics, University Medical Center, Utrecht, The Netherlands.

Objective: To find the underlying defect in a case of primary FSH deficiency and to estimate the beneficial effect of FSH treatment.

Design: Case report.

Setting: University hospital fertility clinic.

Patient(s): Normal, healthy, 37-year-old male patient with severe oligoteratozoospermia.

Intervention(s): Levels of FSH, LH, LHRH provocation test, karyotyping, genomic analysis on the Y-chromosomal AZF region and sequencing of the FSHB gene, FSH treatment.

Main Outcome Measure(s): We compiled detailed clinical and molecular data on four pregnancies. We compare this case with a similar case published recently.

Result(s): There were detectable but very low FSH levels after LHRH provocation; the LH response was not entirely normal, and no genomic abnormalities were found in the FSHB gene. The FSH treatment resulted in four pregnancies, two of which ended in abortion; the other two resulted in the birth of two healthy children. Both our case and the published case had detectable but abnormally low FSH levels on some occasions, but normal or highly normal inhibin B levels that differed from the expected low levels. Both patients had a normal male phenotype and no detectable mutation in the FSHB gene. The published case differed from our patient in that the published case was azoospermic whereas ours was extremely oligoteratozoospermic. The beneficial effect of FSH treatment was only shown in our patient.

Conclusion(s): The published case and ours may have a common, as yet unidentified, underlying defect. The dramatic and immediate effect of FSH treatment on our patient's fertility was clearly demonstrated.
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http://dx.doi.org/10.1016/j.fertnstert.2003.07.030DOI Listing
March 2004

No pathogenic mutations in the uroplakin III gene of 25 patients with primary vesicoureteral reflux.

J Urol 2004 Feb;171(2 Pt 1):931-2

Department of Medical Genetics, University Medical Center Utrect, The Netherlands.

Purpose: The uroplakin III (UPIII) knockout mouse provides a good model for human primary vesicoureteral reflux (VUR). Since to our knowledge no causative genes in human VUR have been identified to date, we wondered whether the UPIII gene might be involved in human primary VUR. Therefore, the UPIII gene was sequenced to see if any mutations could be detected in patients with primary VUR.

Materials And Methods: DNA was obtained from 25 patients who were surgically treated for primary VUR. Each patient had a family history positive for VUR.

Results: No pathogenic mutations were identified in patient DNA. One missense mutation (Ala154Pro) not reported in the human genome data base was observed. However, because its frequency in the patient and control populations was similar, it was interpreted as a polymorphism.

Conclusions: Although mutations in regulatory elements affecting gene function cannot be excluded, the UPIII gene does not seem to have a major role in primary VUR in humans.
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http://dx.doi.org/10.1097/01.ju.0000094802.50650.3dDOI Listing
February 2004

Two cases with partial trisomy 9p: molecular cytogenetic characterization and clinical follow-up.

Am J Med Genet 2002 Apr;109(2):125-32

Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands.

This paper describes two patients with partial trisomy 9p and partial trisomy 14q due to 3:1 segregation from de novo maternal reciprocal translocations. The breakpoints are different from previously described 9;14 translocations and their 3:1 segregation products. The clinical phenotype of both cases is compatible with the partial trisomy 9p syndrome. We present the follow-up of both patients from birth up to age 7 years. Partial trisomy 9p is a frequently described chromosome abnormality. This does not appear to be related to a breakage sensitive locus on chromosome 9p, since the trisomic fragments of the published cases are heterogeneous. In the two cases described here, GTG-banded karyotyping suggested that the 9p breakpoints were similar; DNA marker analysis, however, showed them to be different. Such DNA studies will be necessary to define the genotype-phenotype relation in partial trisomy 9p syndrome.
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http://dx.doi.org/10.1002/ajmg.10322DOI Listing
April 2002
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