72 results on '"Edwin Reyniers"'
Search Results
2. Expression profiling suggests underexpression of the GABAA receptor subunit δ in the fragile X knockout mouse model
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Ilse Gantois, Jo Vandesompele, Frank Speleman, Edwin Reyniers, Rudi D'Hooge, Lies-Anne Severijnen, Rob Willemsen, Flora Tassone, and R. Frank Kooy
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Fragile X syndrome ,Fragile X knockout mouse ,GABAA receptor subunit δ ,Rho guanine exchange factor 12 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
It is still unclear why absence of the fragile X protein (FMRP) leads to mental retardation and specific behavioral problems. In neurons, the protein transports specific mRNAs towards the actively translating ribosomes near the synapses.To unravel the mechanism leading to the disorder, we performed global gene expression analysis by means of the differential display method using the fragile X mouse model. To verify differential expression, we used microarray technology and real-time PCR. Three differentially expressed cDNAs showed consistent underexpression in the fragile X knockout mouse, including a GABAA receptor subunit δ, a Rho guanine exchange factor 12 and an EST BU563433. In addition, we identified 5 genes that showed differential expression dependent on the sample of RNA analysis. We consider their differential expression as provisional. It is possible that these differentially expressed genes play an important role in the cognitive and behavioral problems observed in the fragile X syndrome.
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- 2006
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3. FRA2A is a CGG repeat expansion associated with silencing of AFF3.
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Sofie Metsu, Liesbeth Rooms, Jacqueline Rainger, Martin S Taylor, Hemant Bengani, David I Wilson, Chandra Sekhar Reddy Chilamakuri, Harris Morrison, Geert Vandeweyer, Edwin Reyniers, Evelyn Douglas, Geoffrey Thompson, Eric Haan, Jozef Gecz, David R Fitzpatrick, and R Frank Kooy
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Genetics ,QH426-470 - Abstract
Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship.
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- 2014
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4. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections
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Luciana Young, Milan Prsa, Kathryn Waitzman, Andrea Superti-Furga, Rami Dhillon, Julie Richer, Martin Lammens, Harry C. Dietz, Aline Verstraeten, Geert Mortier, Geert Vandeweyer, Larry W Markham, Lut Van Laer, Josephina A.N. Meester, Julie Vogt, Simon De Belder, Bart Loeys, Isabel Pintelon, Lana Van Hoorick, Luc M. Beauchesne, Wim Wuyts, Edwin Reyniers, and Sheila Unger
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Aneurysm, Dissecting/genetics ,Aneurysm, Dissecting/metabolism ,Aortic Aneurysm, Thoracic/genetics ,Aortic Aneurysm, Thoracic/metabolism ,Biglycan/genetics ,Biglycan/metabolism ,Cells, Cultured ,Female ,Genes, X-Linked ,Genetic Predisposition to Disease ,Humans ,Male ,Mutation ,Pedigree ,Sequence Analysis, DNA/methods ,Signal Transduction ,Transforming Growth Factor beta/metabolism ,0301 basic medicine ,Marfan syndrome ,Pathology ,medicine.medical_specialty ,thoracic aortic aneurysm ,macromolecular substances ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Loeys–Dietz syndrome ,Thoracic aortic aneurysm ,03 medical and health sciences ,Aortic aneurysm ,0302 clinical medicine ,Aneurysm ,Transforming Growth Factor beta ,medicine ,cardiovascular diseases ,Original Research Article ,Genetics (clinical) ,Loss function ,Aortic Aneurysm, Thoracic ,business.industry ,BGN ,Biglycan ,Sequence Analysis, DNA ,musculoskeletal system ,medicine.disease ,biglycan ,Loeys-Dietz syndrome ,carbohydrates (lipids) ,Aortic Dissection ,030104 developmental biology ,cardiovascular system ,Human medicine ,business ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 175552.pdf (Publisher’s version ) (Open Access) PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-beta signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-beta signaling.Genet Med 19 4, 386-395.
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- 2017
5. Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum
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Diane Beysen, Ilse De Veuster, Edwin Reyniers, Sofie Demeulenaere, Marije Meuwissen, and R. Frank Kooy
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Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Facial Paralysis ,Nonsense mutation ,030105 genetics & heredity ,Corpus callosum ,Corpus Callosum ,03 medical and health sciences ,Ptosis ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Animals ,Humans ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing ,Coloboma ,business.industry ,Infant ,Nuclear Proteins ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Blepharophimosis ,Chromatin ,Hypoplasia ,DNA-Binding Proteins ,Developmental disorder ,Facial Nerve ,030104 developmental biology ,Codon, Nonsense ,Child, Preschool ,Mutation ,Female ,Human medicine ,Agenesis of Corpus Callosum ,medicine.symptom ,business - Abstract
Mutations in the chromatin regulator gene BRPF1 were recently associated with the Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis (IDDDFP). Up till now, clinical data of 22 patients are reported. Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features. Animal studies indicate BRPF1 as an important mediator in brain development. However, only 5 of 22 previously reported patients show structural brain abnormalities. We report on an additional patient harboring a novel de novo nonsense mutation p.(Glu219*) in BRPF1. He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum. Our findings support previous findings of brain abnormalities in BRPF1-mutations and indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome.
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- 2019
6. CNV-WebStore: Online CNV Analysis, Storage and Interpretation.
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Geert Vandeweyer, Edwin Reyniers, Wim Wuyts, Liesbeth Rooms, and R. Frank Kooy
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- 2011
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7. PLCB1 epileptic encephalopathies; Review and expansion of the phenotypic spectrum
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An-Sofie Schoonjans, Marije E.C. Meuwissen, Edwin Reyniers, Berten Ceulemans, and R. Frank Kooy
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Male ,0301 basic medicine ,Heterozygote ,Pediatrics ,medicine.medical_specialty ,PLCB1 ,Developmental Disabilities ,Phospholipase C beta ,Status epilepticus ,Bioinformatics ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Intellectual Disability ,Intellectual disability ,medicine ,Humans ,Biology ,business.industry ,Homozygote ,Infant ,General Medicine ,medicine.disease ,Hypsarrhythmia ,030104 developmental biology ,Mutation ,Pediatrics, Perinatology and Child Health ,Etiology ,Human medicine ,Neurology (clinical) ,medicine.symptom ,business ,Haploinsufficiency ,Spasms, Infantile ,Developmental regression ,030217 neurology & neurosurgery - Abstract
Background Biallelic loss-of-function mutations of phospholipase C-β1 ( PLCB1 ) have been described in three children with an early onset epileptic encephalopathy (EE). In two of them a homozygous deletion of the promotor and first three coding exons was found. The third patient had an almost identical heterozygous deletion in combination with a heterozygous splice site variant. All patients had intractable epilepsy and a severe developmental delay. Methods and results We present the case of a boy with an infantile EE starting at the age of four months with a fever induced status epilepticus, modified hypsarrhythmia and developmental regression. The epilepsy was reasonably controlled with corticoids and valproate whereupon generalized tonic-clonic seizures appeared only each 3–4 months. However, only a slow developmental progress was seen hereafter, resulting in a severe intellectual disability with absent speech, motor delay and autistic features. We identified a novel homozygous partial deletion of PLCB1 , affecting exons 7–9. Conclusions This report emphasizes the role of PLCB1 haploinsufficiency in severe EE. We demonstrate a phenotypic variability in patients with a PLCB1 -associated EE. In addition, our findings underscore the importance of microarray analysis in all patients with an EE of unknown etiology.
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- 2016
8. A higher rare CNV burden in the genetic background potentially contributes to intellectual disability phenotypes in 22q11.2 deletion syndrome
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Santhosh Girirajan, Tony J. Simon, Edwin Reyniers, R. Frank Kooy, Flora Tassone, and Matthew Jensen
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0301 basic medicine ,DNA Copy Number Variations ,Intellectual and Developmental Disabilities (IDD) ,Clinical Sciences ,Biology ,Genome ,Article ,Intellectual disabilities ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,DiGeorge syndrome ,Intellectual Disability ,Intellectual disability ,medicine ,DiGeorge Syndrome ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Deletion syndrome ,Copy-number variation ,Copy number variations ,Aetiology ,Intellectual and Developmental Disabilities ,22q11DS ,Gene ,Genetics (clinical) ,Pediatric ,Genetics & Heredity ,Human Genome ,General Medicine ,medicine.disease ,Phenotype ,Brain Disorders ,030104 developmental biology ,Mental Health ,Human medicine ,Chromosome 22 ,030217 neurology & neurosurgery - Abstract
The 22q11.2 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by a hemizygous deletion of 30-40 contiguous genes on chromosome 22, many of which have not been well characterized. Clinical features seen in patients with this deletion, including intellectual disability, are not completely penetrant and vary in severity between patients, suggesting the involvement of variants elsewhere in the genome in the manifestation of the phenotype. Given that it is a relatively rare disorder (1/2000-6000 in humans), limited research has shed light into the contribution of these second-site variants to the developmental pathogenesis that underlies 22q11DS. As CNVs throughout the genome might constitute such a genetic risk factor for variability in the 22q11DS phenotypes such as intellectual disability, we sought to determine if the overall burden of rare CNVs in the genetic background influenced the phenotypic variability. We analyzed CNV and clinical data from 66 individuals with 22q11DS, and found that 77% (51/66) of individuals with the 22q11DS also carry additional rare CNVs (< 0.1% frequency). We observed several trends between CNV burden and phenotype, including that the burden of large rare CNVs (> 200 Kb in size) was significantly higher in 22q11DS individuals with intellectual disability than with normal IQ. Our analysis shows that rare CNVs may contribute to intellectual disability 22q11DS, and further analysis on larger 22q11DS cohorts should be performed to confirm this correlation.
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- 2018
9. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature
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Matthieu P. Robert, Salima El Chehadeh, Geert Vandeweyer, Candace Bensignor, Wilhelmina S. Kerstjens-Frederikse, Darina Prchalova, Hélène Dollfus, Jean-Baptiste Rivière, Christel Thauvin-Robinet, Paul Kuentz, Edwin Reyniers, Patrick Calvas, Caroline Bonnet, Marketa Havlovicova, Rodica Isaiko, Vincent Laugel, Nicolas Chassaing, Julien Thevenon, Christian Gilissen, Morgane Straub, Laurence Faivre, Yannis Duffourd, Miroslava Hancarova, Bart Loeys, R. Frank Kooy, Ange-Line Bruel, Rolph Pfundt, Catherine Creuzot-Garcher, Jolien S. Klein Wassink-Ruiter, Zdenek Sedlacek, FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Service de pédiatrie (CHU de Dijon), Service d'Ophtalmologie (CHU de Dijon), Service de Cardiologie (hôpital général, CHU Dijon), Hôpital général (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Service de Cardiologie, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,Male ,MESH: Heart Defects, Congenital / physiopathology ,Microcephaly ,Pathology ,MESH: Heart Defects, Congenital / genetics ,MESH: Exome / genetics ,030105 genetics & heredity ,MESH: RNA Splicing / genetics ,Microphthalmia ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,MESH: Child ,Exome ,MESH: RNA Splicing Factors / genetics ,Child ,Frameshift Mutation ,MESH: High-Throughput Nucleotide Sequencing ,Genetics (clinical) ,Exome sequencing ,Coloboma ,MESH: Frameshift Mutation ,High-Throughput Nucleotide Sequencing ,Microdeletion syndrome ,Microcephaly, Verheij syndrome, PUF60 ,Chemistry ,Phenotype ,Child, Preschool ,DISEASES ,Medical genetics ,Female ,RNA Splicing Factors ,medicine.symptom ,Chromosome Deletion ,Chromosomes, Human, Pair 8 ,MESH: Dwarfism / genetics ,Heart Defects, Congenital ,medicine.medical_specialty ,GENES ,Adolescent ,RNA Splicing ,MESH: Chromosome Deletion ,Dwarfism ,Biology ,MESH: Phenotype ,Short stature ,Article ,PUF60 ,03 medical and health sciences ,Internal medicine ,Intellectual Disability ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,Genetics ,medicine ,Humans ,Craniofacial ,MESH: Adolescent ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,MESH: Humans ,MESH: Child, Preschool ,medicine.disease ,MESH: Repressor Proteins / genetics ,MESH: Male ,Repressor Proteins ,030104 developmental biology ,Endocrinology ,MESH: Chromosomes, Human, Pair 8 / genetics ,MESH: Dwarfism / physiopathology ,MESH: Intellectual Disability / physiopathology ,Human medicine ,MESH: Intellectual Disability / genetics ,Verheij syndrome ,MESH: Female ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Item does not contain fulltext Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.
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- 2017
10. Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability
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Arjan P.M. de Brouwer, Céline Helsmoortel, Ajay Anand Kumar, Geert Mortier, Edwin Reyniers, Tjitske Kleefstra, Geeit Vandeweyer, Sandra Janssens, Hans van Bokhoven, Ilse M. van der Werf, Anke Van Dijck, R. Frank Kooy, and Vera M. Kalscheuer
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Adult ,Male ,0301 basic medicine ,Adolescent ,Autism Spectrum Disorder ,X-linked intellectual disability ,Population ,Gene Expression ,Pedigree chart ,Disease ,030105 genetics & heredity ,Biology ,medicine.disease_cause ,Severity of Illness Index ,03 medical and health sciences ,Genes, X-Linked ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Articulation Disorders ,Exome ,Genetic Predisposition to Disease ,Child ,education ,Mutation ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Base Sequence ,Genetic heterogeneity ,Sequence Analysis, DNA ,General Medicine ,Middle Aged ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,Phenotype ,030104 developmental biology ,Autism ,Female ,Human medicine ,Genome-Wide Association Study - Abstract
Item does not contain fulltext Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID.
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- 2017
11. Haploinsufficiency of CMIP in a Girl With Autism Spectrum Disorder and Developmental Delay due to a De Novo Deletion on Chromosome 16q23.2
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Geert Vandeweyer, Geert Mortier, Edwin Reyniers, Nathalie Van der Aa, Lina Dom, Liesbeth Rooms, Sandra Kenis, and R. Frank Kooy
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Genetics ,Language delay ,General Neuroscience ,Epigenetics of autism ,Specific language impairment ,medicine.disease ,Autism spectrum disorder ,medicine ,Autism ,Heritability of autism ,Neurology (clinical) ,Psychology ,Haploinsufficiency ,Genetics (clinical) ,Giant axonal neuropathy - Abstract
In a developmentally delayed girl with an autism spectrum disorder, Single nucleotide polymorphism (SNP) array analysis showed a de novo 280 kb deletion on chromosome 16q23.2 involving two genes, GAN and CMIP. Inactivating mutations in GAN cause the autosomal recessive disorder giant axonal neuropathy, not present in our patient. CMIP was recently implicated in the etiology of specific language impairment by genome-wide association analysis. It modulates phonological short-term memory and hence plays an important role in language acquisition. Overlaps of specific language impairment and autism have been debated in the literature regarding the phenotypical language profile as well as etiology. Our patient illustrates that haploinsufficiency of CMIP may contribute to autism spectrum disorders. Our finding further supports the existence of a genetic overlap in the etiology of specific language impairment and autism.
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- 2012
12. Array-based MLPA to detect recurrent copy number variations in patients with idiopathic mental retardation
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Edwin Reyniers, Kurt van Mol, R. Frank Kooy, Geert Vandeweyer, Rudi Rossau, Liesbeth Rooms, Ilse De Canck, and Nathalie Van der Aa
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Genetics ,business.industry ,Microarray Analysis ,medicine.disease ,Subtelomere ,Fragile X syndrome ,genomic DNA ,Intellectual Disability ,Humans ,Medicine ,In patient ,Multiplex ,Human genome ,Human medicine ,Multiplex ligation-dependent probe amplification ,Copy-number variation ,Chromosome Deletion ,DNA Probes ,business ,Biology ,Algorithms ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,DNA Primers - Abstract
Microdeletions, either subtelomeric or interstitial, are responsible for the mental handicap in approximately 1020% of all patients. Currently, Multiplex Ligation-dependent Probe Amplification (MLPA) is widely used to detect these small aberrations in a routine fashion. Although cost-effective, the throughput is low and the degree of multiplexing is limited to maximally 4050 probes. Therefore, we developed an array-based MLPA method, with probes identified by unique tag sequences, allowing the simultaneous analysis of 180 probes in a single experiment thereby covering all known mental retardation loci with at least two probes. We screened 120 patients with idiopathic mental retardation. In this group we detected 6 aberrations giving a detection rate of 5%, consistent with similar studies. In addition we tested 293 patients with mental retardation who were negative for fragile X syndrome and commercially available subtelomeric MLPA. We found seven causative rearrangements in this group (detection rate of 2.4%) thereby illustrating the value of including probes for interstitial microdeletion syndromes and additional probes in the telomeric regions in targeted screening sets for mental retardation. Array-based MLPA may thus be a good candidate to develop probe sets that rapidly detect copy number changes of disease associated loci in the human genome. This method may become a valuable tool in a routine diagnostic setting as it is a fast, user-friendly and relatively low-cost technique providing straightforward results requiring only 125 ng of genomic DNA.
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- 2011
13. Hereditary angioedema in 2 sisters due to paternal gonadal mosaicism
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Esther Bartholomeus, Vito Sabato, Hélène Poirel, Edwin Reyniers, Athina L. Van Gasse, Jean-François Vanbellinghen, Didier G. Ebo, Geert Mortier, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - SSS/DDUV/GEHU - Génétique
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0301 basic medicine ,endocrine system ,medicine.medical_specialty ,urogenital system ,business.industry ,Germline mosaicism ,medicine.disease ,Dermatology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Hereditary angioedema ,medicine ,Immunology and Allergy ,Human medicine ,business - Abstract
We report the occurrence of type I hereditary angioedema in 2 sisters with unaffected parents caused by paternal gonadal mosaicism. Gonadal mosaicism is a rather uncommon genetic phenomenon, but nevertheless, correct diagnosis is important because it may affect further family planning.
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- 2018
14. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome
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Bregje W.M. van Bon, Tiia Reimand, Berten Ceulemans, Barbara Delle Chiaie, Christine Oley, Anne Destree, Ernie M.H.F. Bongers, Danielle Martinet, Dom McMullan, Rolph Pfund, Bert B.A. de Vries, Jenneke van den Ende, Louise Brueton, Connie Schrander-Stumpel, Corrado Romano, Marco Fichera, Alexander P.A. Stegmann, Edwin Reyniers, Geert Mortier, Suzanna G.M. Frints, Isabelle Maystadt, Katrin Männik, Nathalie Van der Aa, Ants Kurg, Geert Vandeweyer, Björn Menten, Alessandra Ferrarini, R. Frank Kooy, Sébastien Jacquemont, and Liesbeth Rooms
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Male ,Williams Syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,Pediatrics ,medicine.medical_specialty ,Language delay ,Population ,Chromosome Disorders ,Speech Disorders ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Communication disorder ,Intellectual Disability ,Gene duplication ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Diaphragmatic hernia ,Child ,education ,Genetics (clinical) ,Family Health ,education.field_of_study ,business.industry ,Infant ,Syndrome ,General Medicine ,medicine.disease ,Hypotonia ,Phenotype ,Child, Preschool ,Face ,Speech delay ,Autism ,Female ,Human medicine ,Chromosome Deletion ,medicine.symptom ,business ,Chromosomes, Human, Pair 7 - Abstract
Contains fulltext : 80644.pdf (Publisher’s version ) (Closed access) Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.
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- 2009
15. The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior
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Charles E. Schwartz, Alfons Meindl, Claus Lenski, Heide Hellebrand, Birgitta Winnepenninckx, Daniela Loessner, Stefanie Engert, R. Frank Kooy, Edwin Reyniers, Juliane Ramser, Ronald J.A. Wanders, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Laboratory Genetic Metabolic Diseases
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Male ,Genetic Linkage ,Choreoathetosis ,Gene Expression ,Biology ,medicine.disease_cause ,HSD17B10 ,Exon ,Report ,Gene expression ,Genetics ,medicine ,Humans ,Missense mutation ,Genetics(clinical) ,Gene ,Chorea Gravidarum ,Genetics (clinical) ,X chromosome ,Behavior ,Mutation ,Mental Disorders ,3-Hydroxyacyl CoA Dehydrogenases ,Syndrome ,Pedigree ,Mental Retardation, X-Linked ,Female ,medicine.symptom - Abstract
Recently, we defined a new syndromic form of X-linked mental retardation in a 4-generation family with a unique clinical phenotype characterized by mild mental retardation, choreoathetosis, and abnormal behavior (MRXS10). Linkage analysis in this family revealed a candidate region of 13.4 Mb between markers DXS1201 and DXS991 on Xp11; therefore, mutation analysis was performed by direct sequencing in most of the 135 annotated genes located in the region. The gene (HADH2) encoding L-3-hydroxyacyl-CoA dehydrogenase II displayed a sequence alteration (c.574 C-->A; p.R192R) in all patients and carrier females that was absent in unaffected male family members and could not be found in 2,500 control X chromosomes, including in those of 500 healthy males. The silent C-->A substitution is located in exon 5 and was shown by western blot to reduce the amount of HADH2 protein by 60%-70% in the patient. Quantitative in vivo and in vitro expression studies revealed a ratio of splicing transcript amounts different from those normally seen in controls. Apparently, the reduced expression of the wild-type fragment, which results in the decreased protein expression, rather than the increased amount of aberrant splicing fragments of the HADH2 gene, is pathogenic. Our data therefore strongly suggest that reduced expression of the HADH2 protein causes MRXS10, a phenotype different from that caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, which is a neurodegenerative disorder caused by missense mutations in this multifunctional protein
- Published
- 2007
16. Expression profiling suggests underexpression of the GABAA receptor subunit δ in the fragile X knockout mouse model
- Author
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Edwin Reyniers, Lies Anne Severijnen, R. Frank Kooy, Rob Willemsen, Jo Vandesompele, Flora Tassone, Ilse Gantois, Rudi D'Hooge, Frank Speleman, and Clinical Genetics
- Subjects
Male ,Rho guanine exchange factor 12 ,Protein subunit ,Biology ,GABAA receptor subunit δ ,lcsh:RC321-571 ,Fragile X Mental Retardation Protein ,Mice ,Receptors, GABA ,Sequence Homology, Nucleic Acid ,Gene expression ,medicine ,Animals ,Humans ,Fragile X knockout mouse ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Gene ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Differential display ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Brain ,medicine.disease ,Immunohistochemistry ,Molecular biology ,Fragile X syndrome ,Gene expression profiling ,Disease Models, Animal ,Neurology ,Fragile X Syndrome ,Knockout mouse ,Gene chip analysis - Abstract
It is still unclear why absence of the fragile X protein (FMRP) leads to mental retardation and specific behavioral problems. In neurons, the protein transports specific mRNAs towards the actively translating ribosomes near the synapses. To unravel the mechanism leading to the disorder, we performed global gene expression analysis by means of the differential display method using the fragile X mouse model. To verify differential expression, we used microarray technology and real-time PCR. Three differentially expressed cDNAs showed consistent underexpression in the fragile X knockout mouse, including a GABAA receptor subunit δ, a Rho guanine exchange factor 12 and an EST BU563433. In addition, we identified 5 genes that showed differential expression dependent on the sample of RNA analysis. We consider their differential expression as provisional. It is possible that these differentially expressed genes play an important role in the cognitive and behavioral problems observed in the fragile X syndrome.
- Published
- 2006
17. Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities
- Author
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Kellie A Davis, Stefaan Scheers, Kiana Siefkas, Edwin Reyniers, Jill A. Rosenfeld, Ilse M. van der Werf, Meron Azage, A. Micheil Innes, R. Frank Kooy, Marije E.C. Meuwissen, Geert Mortier, Bob Argiropoulos, Nathalie Van der Aa, Amy Lacroix, Anke Van Dijck, and Heather C Mefford
- Subjects
Male ,Microcephaly ,Trisomy ,Biology ,Craniofacial Abnormalities ,Gene duplication ,Intellectual disability ,Genetics ,medicine ,Humans ,Megalencephaly ,Child ,Genetics (clinical) ,Macrocephaly ,Infant ,General Medicine ,Syndrome ,Twins, Monozygotic ,Overweight ,medicine.disease ,Penetrance ,Chromosomes, Human, Pair 1 ,Child, Preschool ,Autism ,Female ,Human medicine ,medicine.symptom - Abstract
Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intra-chromosomal recombination. (C) 2015 Elsevier Masson SAS. All rights reserved.
- Published
- 2014
18. Multiplex ligation-dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics
- Author
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R van Luijk, Jan Wauters, Annick Laridon, Stefaan Scheers, J. van den Ende, Berten Ceulemans, Wim Wuyts, Katrien Storm, G. Van Goethem, Winnie Courtens, François Eyskens, Liesbeth Rooms, Edwin Reyniers, R.F. Kooy, and Martine Biervliet
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.diagnostic_test ,Hybridization probe ,Karyotype ,Biology ,Subtelomere ,Molecular biology ,Gene duplication ,medicine ,Multiplex ligation-dependent probe amplification ,Molecular probe ,Ligase chain reaction ,Genetics (clinical) ,Genetic testing - Abstract
Subtelomeric rearrangements are believed to be responsible for 5-7% of idiopathic mental retardation cases. Due to the relative complexity and high cost of the screening methods used till now, only preselected patient populations including mostly the more severely affected cases have been screened. Recently, multiplex ligation-dependent probe amplification (MLPA) has been adapted for use in subtelomeric screening, and we have incorporated this technique into routine diagnostics of our laboratory. Since the evaluation of MLPA as a screening method, we tested 275 unselected patients with idiopathic mental retardation and detected 12 possible subtelomeric aberrations: a der(11)t(11;20)(qter;qter), a 19pter duplication, a der(18)t(18;10)(qter; pter), a 15qter deletion, a 8pter deletion, a 6qter deletion, a der(X)t(X;1)(pter;qter), a der(X)t(X;3)(pter;pter), a 5qter duplication, a 3pter deletion, and two 3qter duplications. The patients can be subdivided into two groups: the first containing de novo rearrangements that are likely related to the clinical presentation of the patient and the second including aberrations also present in one of the parents that may or may not be causative of the mental retardation. In our patient cohort, five (1.8%) subtelomeric rearrangements were de novo, three (1.1%) rearrangements were familial and suggestively disease causing, and four (1.5%) were possible polymorphisms. This high frequency of subtelomeric abnormalities detected in an unselected population warrants further investigation about the feasibility of routine screening for subtelomeric aberrations in mentally retarded patients.
- Published
- 2005
19. Subtelomeric rearrangements in the mentally retarded: A comparison of detection methods
- Author
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Edwin Reyniers, Liesbeth Rooms, and R. Frank Kooy
- Subjects
Chromosome Aberrations ,Genetics ,medicine.diagnostic_test ,Nucleic Acid Hybridization ,Karyotype ,DNA ,Mentally retarded ,Telomere ,Biology ,Subtelomere ,Molecular biology ,Intellectual Disability ,medicine ,Humans ,Multiplex ,Genetic Testing ,Multiplex ligation-dependent probe amplification ,Alleles ,Genetics (clinical) ,Comparative genomic hybridization ,Fluorescence in situ hybridization - Abstract
In recent years, subtelomeric rearrangements, e.g., chromosome deletions or duplications too small to be detected by conventional cytogenetic analysis, have emerged as a significant cause of both idiopathic and familial mental retardation. As mental retardation is a common disorder, many patients need to be tested on a routine basis. In this review, we will discuss the different methods that have been applied in laboratories worldwide, including multiprobe fluorescence in situ hybridization (FISH), multiallelic marker analysis, multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), quantitative real-time PCR, comparative genomic hybridization (CGH), and multicolor FISH, including spectral karyotyping (SKY), subtelomeric combined binary ratio labeling FISH (S-COBRA FISH), multiplex FISH telomere integrity assay (M-TEL), telomeric multiplex FISH (TM-FISH), and primed in situ labeling (PRINS).
- Published
- 2005
20. Familial hypertryptasemia with associated mast cell activation syndrome
- Author
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Edwin Reyniers, Didier G. Ebo, Erik Fransen, Luc S. De Clerck, Vito Sabato, Els van de Vijver, Peter Valent, Geert Mortier, Chris H. Bridts, Inge Vrelust, and Margo M. Hagendorens
- Subjects
Adult ,Male ,Adolescent ,Genotype ,Genetic Linkage ,Immunology ,MEDLINE ,Mast cell activation syndrome ,Young Adult ,Text mining ,Metabolic Diseases ,Genetic linkage ,Immunology and Allergy ,Medicine ,Humans ,Young adult ,business.industry ,Infant ,Middle Aged ,Pedigree ,Child, Preschool ,Female ,Tryptases ,Human medicine ,medicine.symptom ,business ,Mastocytosis - Published
- 2014
21. FRA2A is a CGG repeat expansion associated with silencing of AFF3
- Author
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Evelyn Douglas, David I. Wilson, Harris Morrison, Chandra Sekhar Reddy Chilamakuri, R. Frank Kooy, Hemant Bengani, Sofie Metsu, Geert Vandeweyer, Liesbeth Rooms, Eric Haan, Geoffrey N. Thompson, David R. FitzPatrick, Edwin Reyniers, Martin S. Taylor, Jacqueline K. Rainger, and Jozef Gecz
- Subjects
Male ,Cancer Research ,lcsh:QH426-470 ,Bisulfite sequencing ,Gene Identification and Analysis ,Gene Expression ,Fos-Related Antigen-2 ,Biology ,Polymorphism, Single Nucleotide ,Molecular Genetics ,Intellectual Disability ,medicine ,Genetics ,Humans ,Allele ,Promoter Regions, Genetic ,Molecular Biology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Alleles ,Chromosomal fragile site ,Chromosome Fragile Sites ,Nuclear Proteins ,Biology and Life Sciences ,DNA Methylation ,medicine.disease ,Molecular biology ,Fragile X syndrome ,lcsh:Genetics ,Phenotype ,Chromosome Fragile Site ,DNA methylation ,Female ,Epigenetics ,Human medicine ,Haploinsufficiency ,Trinucleotide repeat expansion ,Trinucleotide Repeat Expansion ,Research Article - Abstract
Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5–12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship., Author Summary Some human genetic diseases are caused by dynamic mutations, or expansions of a short repeated sequence in the genome that can be unstably passed on from generation to generation. A subset of these dynamic mutations known as fragile sites can be seen as a break or gap on the chromosome when cells are cultured under specific conditions. To date eight folate-sensitive fragile sites (FSFS) have been characterized, and all are due to CGG-repeat expansions within the 5′ UTR or promoter region of the respective gene. When the repeat expands in size, it becomes hypermethylated and the adjacent gene or genes are transcriptionally silenced. For at least four of the eight known fragile sites this silencing of the associated gene(s) lead to intellectual disability syndromes such as fragile X. In this work we describe molecular characterization of an autosomal FSFS called FRA2A on chromosome 2. As the molecular cause of FRA2A, we identify an expansion of a CGG repeat which subsequently results in silencing of the neighbouring gene AFF3. This gene is one of the four autosomal paralogss of the AFF2/FMR2 gene which, when mutated, is the cause of the FRAXE syndrome. We find that FRA2A expression is associated with highly variable developmental anomalies in the three FRA2A families studied.
- Published
- 2014
22. Restoring the Phenotype of Fragile X Syndrome: Insight from the Mouse Model
- Author
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Ben A. Oostra, R.F. Kooy, Cathy E. Bakker, Rudi D'Hooge, Ilse Gantois, Ruben H. Willemsen, P.P. De Deyn, Edwin Reyniers, and Clinical Genetics
- Subjects
Male ,DNA, Complementary ,Transgene ,Genetic Vectors ,Gene Expression ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Biochemistry ,Fragile X Mental Retardation Protein ,Mice ,Cognition ,Testis ,Gene expression ,medicine ,Animals ,Humans ,Chromosomes, Artificial, Yeast ,Molecular Biology ,Gene knockout ,Mice, Knockout ,Genetics ,Behavior, Animal ,Macroorchidism ,RNA-Binding Proteins ,Genetic Therapy ,General Medicine ,medicine.disease ,FMR1 ,Phenotype ,Fragile X syndrome ,Disease Models, Animal ,Fragile X Syndrome ,Knockout mouse ,Molecular Medicine - Abstract
A mouse model for the fragile X syndrome, the most common form of inherited mental retardation, was generated a number of years ago. It shows characteristics compatible with the clinical symptoms of human patients. These include pathological changes such as macroorchidism, behavioral problems, and diminished visuo-spatial abilities. To investigate whether the fragile X syndrome is a potentially correctable disorder, several groups attempted to 'rescue' the knockout mutation by introduction of an intact copy of the FMR1 gene in the knockout mouse. Two different types of rescue mice have been created by injection of constructs based on FMR1 cDNA or on FMR1 genomic DNA. Several pathological, behavioral and cognitive function tests were performed on these two different rescue mouse lines to compare their characteristics with those of the knockout and control littermates. Each rescue line resembled the control in some aspects though neither of the 2 lines was a full 'rescue', e.g. resemble the control in all aspects investigated. Thus, rescue of some aspects of the phenotype has been achieved by introduction of FMR1 constructs in the fragile X knockout mice. The results implicate that, even if FMR1 production is cell type specific, the quantity of the FMRP expression is highly critical as overproduction may have a harmful effect.
- Published
- 2001
23. Precise mapping of the fragile site FRA12A on chromosome 12q13.1
- Author
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Arie P. T. Smits, Birgitta Winnepenninckx, P. Bossuyt, R. Frank Kooy, Jan Wauters, and Edwin Reyniers
- Subjects
Fragile X syndrome ,Fmr1 gene ,Genetics ,Candidate gene ,Contig ,Chromosomal fragile site ,medicine ,In situ hybridization ,Biology ,medicine.disease ,Trinucleotide repeat expansion ,Gene - Abstract
Introduction A causative relationship has been reported between fragile site expression and disease for FRA12A, a rare, folate-sensitive fragile site on chromosome 12q13.1. FRA12A expression has been described in a number of patients with mental retardation, sometimes in combination with clinical abnormalities. In correspondence to the molecular mechanism of previously cloned, rare, fragile sites, it may be expected that FRA12A is caused by repeat expansion, affecting the expression of genes in the region. To identify the repeat and the associated gene, this paper reports the precise mapping of FRA12A on chromosome 12q12–13. Methods Fluorescence in situ hybridization (FISH) techniques were used to map YAC and PAC clones in the neighbourhood of FRA12A. PAC DNA pools and PAC filters were screened to find additional PAC clones spanning the candidate region. Markers in the region were obtained via web searches and used to construct both PAC and YAC contigs. Results and Discussion A single YAC clone that overspans the fragile site was identified and a complete YAC and PAC contig for the FRA12A region was constructed. The region contains several candidate genes, including a calcium ion channel (CACNLB3), a GTP-binding factor (ARF3), a gene involved in brain development (INT1) and two other genes involved in developmental processes (WNT10B and ALR). The FXR1 gene, a homologue of the FMR1 gene, that is associated with fragile X syndrome and that maps to chromosome 12q12–13, was ruled out as a possible candidate gene for the FRA12A site.
- Published
- 2001
24. Introduction of aFMR1 transgene in the fragile X knockout mouse
- Author
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R.F. Kooy, B. B. A. De Vries, P. J. Willems, P.P. De Deyn, Ruben H. Willemsen, Filippo Tamanini, Ingeborg M. Nieuwenhuizen, R. d' Hooge, Edwin Reyniers, B.A. Oostra, A. T. Hoogeveen, and Cathy E. Bakker
- Subjects
Fragile x ,General Neuroscience ,Transgene ,Knockout mouse ,Biology ,Cell biology - Published
- 2000
25. CAG repeat contraction in the androgen receptor gene in three brothers with mental retardation
- Author
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Petra E. de Ruiter, L Vits, R. Frank Kooy, Patrick Willems, Anne De Paepe, Edwin Reyniers, Albert O. Brinkmann, Désirée van Velzen, and Katrien Storm
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,medicine.drug_class ,Biology ,Androgen ,medicine.disease ,Genetic determinism ,nervous system diseases ,Androgen receptor ,Spinal and bulbar muscular atrophy ,Endocrinology ,Internal medicine ,medicine ,Dynamic mutation ,Trinucleotide repeat expansion ,Gene ,Genetics (clinical) ,X chromosome - Abstract
We report on three brothers with mental retardation and a contracted CAG repeat in the androgen receptor (AR) gene. It is known that expansion of the CAG repeat in this gene leads to spinal and bulbar muscular atrophy (SBMA or Kennedy disease); however, contracted repeats have not yet been implicated in disease. As the range of the length of CAG repeats in the AR gene, like those of other genes associated with dynamic mutations, follows a normal distribution, the theoretical possibility of disease at both ends of the distribution should be considered.
- Published
- 1999
26. Neuroanatomy of the fragile X knockout mouse brain studied using in vivo high resolution magnetic resonance imaging
- Author
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Jan Sijbers, Annemie Van der Linden, Patrick Willems, Edwin Reyniers, Marleen Verhoye, Ben A. Oostra, R. Frank Kooy, Cathy E. Bakker, and Clinical Genetics
- Subjects
Male ,Dendritic spine ,Hippocampus ,Ventricular system ,Biology ,Mice ,Image Processing, Computer-Assisted ,Genetics ,medicine ,Animals ,Genetics (clinical) ,Mice, Knockout ,medicine.diagnostic_test ,Brain ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Radiography ,Fragile X syndrome ,Disease Models, Animal ,medicine.anatomical_structure ,Fragile X Syndrome ,Knockout mouse ,Cerebellar vermis ,Neuroscience ,Neuroanatomy - Abstract
Magnetic resonance imaging (MRI) of the brain of fragile X patients, the most frequent form of inherited mental retardation, has revealed abnormalities in the size of specific brain structures, including the cerebellar vermis, the hippocampus, and the ventricular system. We intended to quantify the differences observed in the patient studies in the fragile X knockout mouse model, which is a good model for the disease, paralleling the human disorder in having cognitive deficits, macro-orchidism, and immature dendritic spines. Therefore we set up MRI of the mouse brain which allowed us to measure the size of the brain structures reported to be abnormal in human fragile X patients in the mouse model. We did not find evidence for size alterations in various brain regions of the fragile X mouse model, but the method described may find a wide application in the study of mutant mouse models with neurological involvement.
- Published
- 1999
27. Postmortem examination of two fragile X brothers with anFMR1 full mutation
- Author
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Patrick Cras, I Handig, Eric Van Marck, R. Frank Kooy, Edwin Reyniers, Hugo Z.J. Jorens, Ben A. Oostra, Jean-Jacques Martin, and Patrick Willems
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,Offspring ,Autopsy ,Biology ,medicine.disease_cause ,medicine.disease ,FMR1 ,nervous system diseases ,Fragile X syndrome ,Dynamic mutation ,medicine ,Trinucleotide repeat expansion ,Cerebellar hypoplasia ,Genetics (clinical) - Abstract
Large expansions of the CGG repeat in the 5' untranslated region of the FMR1 gene are found in patients with the fragile X syndrome. Amplified CGG repeats in FMR1 are unstable and show intergenerational increase from mother to offspring. The exact timing of repeat amplification, however, is unknown. We have compared the extent of CGG expansion in various tissues of this deceased fragile X patient, and found only limited variation in repeat expansion. The repeat was fully methylated in all tissues examined. Therefore, no evidence for extensive mitotic expansion of the CGG repeat during fetal or postnatal life of a fragile X patient was found, in contrast to dynamic mutations caused by CAG/CTG repeat expansion. Extensive pathological examination of this patient and his affected brother revealed no evidence for specific abnormalities relevant to fragile X syndrome; cerebellar hypoplasia, which has been reported in this disorder, was not evident in either patient.
- Published
- 1999
28. L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns
- Author
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Edwin Reyniers, Patrick Willems, Annemie Van der Linden, Chris I. De Zeeuw, Peter Paul De Deyn, Erik Fransen, Rudi D'Hooge, Philippe Soriano, Hiroyuki Kamiguchi, Jan Sijbers, Marleen Verhoye, Vance Lemmon, Sebastiaan K. E. Koekkoek, R. Frank Kooy, Rob Willemsen, Guy Van Camp, Clinical Genetics, and Neurosciences
- Subjects
Pathology ,medicine.medical_specialty ,Cell Adhesion Molecules, Neuronal ,Biology ,Ventricular system ,Polymerase Chain Reaction ,Cerebral Ventricles ,Mice ,Lateral ventricles ,Cerebellum ,Neurites ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Mice, Knockout ,Neurologic Examination ,Brain Diseases ,Memory Disorders ,Membrane Glycoproteins ,Behavior, Animal ,General Medicine ,Anatomy ,medicine.disease ,Magnetic Resonance Imaging ,Hypoplasia ,Hydrocephalus ,Mice, Inbred C57BL ,Disease Models, Animal ,Cerebral aqueduct ,Corticospinal tract ,Knockout mouse ,Cerebellar vermis ,Cognition Disorders ,Leukocyte L1 Antigen Complex - Abstract
L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.
- Published
- 1998
29. Positional cloning of a gene involved in hereditary multiple exostoses
- Author
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P. Bossuyt, A. M. W. Van Den Ouweland, D. J. J. Halley, W. Van Hul, L Vits, Jan Wauters, K. De Boulle, Paul Coucke, M. Nemtsova, Wim Wuyts, P. J. Willems, Thomas B. Shows, Edwin Reyniers, Norma J. Nowak, B. B. A. De Vries, L. Mallet, Wendy Balemans, Julie McGaughran, I. Herrygers, E Van Hul, Jan Hendrickx, and Erik Fransen
- Subjects
Yeast artificial chromosome ,DNA, Complementary ,Positional cloning ,Hereditary multiple exostoses ,Molecular Sequence Data ,Biology ,Homology (biology) ,Gene mapping ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,Molecular Biology ,Gene ,Genetics (clinical) ,Base Sequence ,Contig ,Chromosomes, Human, Pair 11 ,General Medicine ,medicine.disease ,Molecular biology ,Open reading frame ,Chromosomes, Human, Pair 19 ,Sequence Alignment ,Exostoses, Multiple Hereditary ,Chromosomes, Human, Pair 8 - Abstract
Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.
- Published
- 1996
30. Long-term potentiation in the hippocampus of fragile X knockout mice
- Author
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P. J. Willems, Ben A. Oostra, P.P. De Deyn, Rudi D'Hooge, Jean-Marie Godfraind, Cathy E. Bakker, K. De Boulle, Edwin Reyniers, and R.F. Kooy
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Morris water navigation task ,Long-term potentiation ,Biology ,Gene mutation ,Hippocampal formation ,FMR1 ,nervous system diseases ,Endocrinology ,Internal medicine ,Knockout mouse ,medicine ,Excitatory postsynaptic potential ,Immediate early gene ,Genetics (clinical) - Abstract
To gain more insight in the physiological function of the fragile X gene (FMR1) and the mechanisms leading to fragile X syndrome, the Fmr1 gene has been inactivated in mice by gene targeting techniques. In the Morris water maze test, the Fmr1 knockout mice learn to find the hidden platform nearly as well as the control animals, but show impaired performance after the position of the platform has been modified. As malperformance in the Morris water maze test has been associated with impaired long-term potentiation (LTP), electrophysiological studies were performed in hippocampal slices of Fmr1 knockout mice to check for the presence of LTP. Judged by field extracellular excitatory postsynaptic potential recordings in the CA1 hippocampal area, Fmr1 knockout mice express LTP to a similar extent as their wild type littermates during the first 1-2 hr after high frequency stimulation. Also, short-term potentiation (STP) was similar in both types of mice. To investigate whether Fmr1 is involved in the latter stages of LTP as an immediate early gene, we compared Fmr1 mRNA quantities on northern blots after chemical induction of seizures. A transient increase in the transcription of immediate early genes is thought to be essential for the maintenance of LTP. As no increase in Fmr1 mRNA could be detected, neither in cortex nor in total brain, during the first 2 1/2 hr after pentylenetetrazol-induced seizures, it is unlikely that Fmr1 is an immediate early gene in mice. In conclusion, we found no evidence for a function of FMR1 in STP or LTP.
- Published
- 1996
31. Transgenic mouse model for the fragile X syndrome
- Author
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Guy Nagels, R. Frank Kooy, Kristel De Boulle, Gilbert Clincke, Rudi D'Hooge, Ben A. Oostra, Edwin Reyniers, Patrick Willems, Peter Paul De Deyn, Katrien Storm, and Cathy E. Bakker
- Subjects
Fragile X syndrome ,Genetically modified mouse ,Genetics ,Macroorchidism ,Transgene ,Knockout mouse ,medicine ,Gene mutation ,Biology ,medicine.disease ,FMR1 ,Genetics (clinical) ,Transgenic Model - Abstract
Transgenic fragile X knockout mice have been constructed to provide an animal model to study the physiologic function of the fragile X gene (FMR1) and to gain more insight into the clinical phenotype caused by the absence of the fragile X protein. Initial experiments suggested that the knockout mice show macroorchidism and cognitive and behavioral deficits, abnormalities comparable to those of human fragile X patients. In the present study, we have extended our experiments, and conclude that the Fmr1 knockout mouse is a reliable transgenic model to study the fragile X syndrome. 20 refs., 2 figs., 1 tab.
- Published
- 1996
32. An animal model for fragilex syndrome
- Author
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Edwin Reyniers, Patrick Willems, and Ben A. Oostra
- Subjects
Genetically modified mouse ,Mutation ,Pathology ,medicine.medical_specialty ,Genetic enhancement ,Mutant ,Biology ,medicine.disease ,medicine.disease_cause ,Bioinformatics ,FMR1 ,Embryonic stem cell ,Fragile X syndrome ,Neuropsychology and Physiological Psychology ,Pediatrics, Perinatology and Child Health ,medicine ,Gene ,Genetics (clinical) - Abstract
Although the fragile X gene (FMR1) was isolated more than four years ago, little is known about its physiologic function and the pathological mechanisms that lead to the abnormalities observed in fragile X patients. To provide more insight into the physiologic role of FMR1, we have developed a transgenic mouse with a loss-of-function (Knockout) mutation in the FMR1 gene using homologous recombination in embryonic stem cells. The mutant mice lack normal FMR1 mRNA and protein, as is also the case in human fragile X syndrome. The mice show enlarged testes and impaired performance in cognitive function tests, a clinical picture very similar to that of human patients. As a consequence, this animal model might be useful in elucidating the physiologic function of FMR1 and the pathological mechanisms that lead to mental retardation and behavioral abnormalities in fragile X syndrome. Experimental drug treatment can now be tried to ameliorate the congnitive function and behavior of affected mice and, if these experiments are successful, human trials can be initiated. Furthermore, gene therapy experiments by introduction of a foreign FMR1 gene into mutant mice can now be begun. © 1995 Wiley-Liss, Inc.
- Published
- 1995
33. Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11
- Author
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Lodewijk A. Sandkuijl, D. J. J. Halley, Martinus F. Niermeijer, Edwin Reyniers, Yuan-Qing Wu, Hans Galjaard, Peter Heutink, B. B. A. De Vries, A. M. W. Van Den Ouweland, and P. J. Willems
- Subjects
Genetic Markers ,Male ,musculoskeletal diseases ,Langer-Giedion Syndrome ,Genetic Linkage ,Hereditary multiple exostoses ,Centromere ,Bone Neoplasms ,Locus (genetics) ,Biology ,Langer–Giedion syndrome ,Gene mapping ,Locus heterogeneity ,Genetic linkage ,Genetics ,medicine ,Humans ,Molecular Biology ,Genetics (clinical) ,X chromosome ,Recombination, Genetic ,Osteosarcoma ,Autosome ,Chromosomes, Human, Pair 11 ,Chromosome Mapping ,General Medicine ,medicine.disease ,Pedigree ,Female ,Chromosome Deletion ,Lod Score ,human activities ,Exostoses, Multiple Hereditary ,Chromosomes, Human, Pair 8 - Abstract
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder of enchondral bone formation characterized by multiple bony outgrowths (exostoses), with progression to osteosarcoma in a minority of cases. The exclusive involvement of skeletal abnormalities distinguishes EXT from the clinically more complex Langer-Giedion syndrome (LGS), which is associated with deletions at chromosome 8q24. Previously, linkage analysis has revealed a locus for EXT in the LGS region on chromosome 8q24. However, locus heterogeneity was apparent with 30% of the families being unlinked to 8q24. We report on two large pedigrees segregating EXT in which linkage to the LGS region was excluded. To localize the EXT gene(s) in these families we performed a genome search including 254 microsatellite markers dispersed over all autosomes and the X chromosome. In both families evidence was obtained for linkage to markers from the proximal short and long arms of chromosome 11. Two-point analysis gave the highest lod score for D11S554 (Zmax = 7.148 at theta = 0.03). Multipoint analysis indicated a map position for the EXT gene between D11S905 and D11S916, with a peak multipoint lod score of 8.10 at 6 cM from D11S935. The assignment of a second locus for EXT to the pericentromeric region of chromosome 11 implicates an area that is particularly rich in genes responsible for developmental abnormalities and neoplasia.
- Published
- 1994
34. Haploinsufficiency of CMIP in a girl with autism spectrum disorder and developmental delay due to a de novo deletion on chromosome 16q23.2
- Author
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Nathalie, Van der Aa, Geert, Vandeweyer, Edwin, Reyniers, Sandra, Kenis, Lina, Dom, Geert, Mortier, Liesbeth, Rooms, and R Frank, Kooy
- Subjects
Developmental Disabilities ,Genetic Carrier Screening ,Infant, Newborn ,Infant ,Exons ,Haploinsufficiency ,Polymorphism, Single Nucleotide ,Cytoskeletal Proteins ,Child Development Disorders, Pervasive ,Child, Preschool ,Humans ,Female ,Language Development Disorders ,Longitudinal Studies ,Chromosome Deletion ,Carrier Proteins ,Chromosomes, Human, Pair 16 ,Adaptor Proteins, Signal Transducing - Abstract
In a developmentally delayed girl with an autism spectrum disorder, Single nucleotide polymorphism (SNP) array analysis showed a de novo 280 kb deletion on chromosome 16q23.2 involving two genes, GAN and CMIP. Inactivating mutations in GAN cause the autosomal recessive disorder giant axonal neuropathy, not present in our patient. CMIP was recently implicated in the etiology of specific language impairment by genome-wide association analysis. It modulates phonological short-term memory and hence plays an important role in language acquisition. Overlaps of specific language impairment and autism have been debated in the literature regarding the phenotypical language profile as well as etiology. Our patient illustrates that haploinsufficiency of CMIP may contribute to autism spectrum disorders. Our finding further supports the existence of a genetic overlap in the etiology of specific language impairment and autism.
- Published
- 2011
35. The full mutation in the FMR–1 gene of male fragile X patients is absent in their sperm
- Author
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Edwin Reyniers, Lieve Vits, Kristel De Boulle, Bernadette Van Roy, Desirée Van Velzen, Esther de Graaff, Annemieke J.M.H. Verkerk, Hugo Z.J. Jorens, John K. Darby, Ben Oostra, and Patrick J. Willems
- Subjects
Fragile X syndrome ,Genetics ,Meiosis ,CpG site ,DNA methylation ,Mutation (genetic algorithm) ,Anticipation (genetics) ,Gene duplication ,medicine ,Biology ,medicine.disease ,Sperm - Abstract
Fragile X syndrome is characterized at the molecular level by amplification of a (CGG)n repeat and hypermethylation of a CpG island preceeding the open reading frame of the fragile X gene (FMR-1) located in Xq27.3. Anticipation in this syndrome is associated with progressive amplification of the (CGG)n repeat from a premutation to a full mutation through consecutive generations. Remarkably, expansion of the premutation to the full mutation is strictly maternal. To clarify this parental influence we studied FMR-1 in sperm of four male fragile X patients. This showed that only the premutation was present in their sperm, although they had a full mutation in peripheral lymphocytes. This might suggest that expansion of the premutation to the full mutation in FMR-1 does not occur in meiosis but in a postzygotic stage.
- Published
- 1993
36. A point mutation in the FMR-1 gene associated with fragile X mental retardation
- Author
-
Edwin Reyniers, L Vits, F Van den Bos, E. de Graaff, B. Van Roy, Anton Verkerk, K. De Boulle, Jan Hendrickx, Patrick Willems, and Ben A. Oostra
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA Mutational Analysis ,Molecular Sequence Data ,Nerve Tissue Proteins ,Biology ,Polymerase Chain Reaction ,Fragile X Mental Retardation Protein ,Genetics ,medicine ,Humans ,Point Mutation ,Amino Acid Sequence ,RNA, Messenger ,Gene ,X chromosome ,Cell Line, Transformed ,Repetitive Sequences, Nucleic Acid ,Base Sequence ,Point mutation ,Chromosomal fragile site ,RNA-Binding Proteins ,DNA ,medicine.disease ,Molecular biology ,Pedigree ,Fragile X syndrome ,Blotting, Southern ,CpG site ,Fragile X Syndrome ,Mutation (genetic algorithm) ,DNA methylation ,Female ,Human medicine - Abstract
The vast majority of patients with fragile X syndrome show a folate-sensitive fragile site at Xq27.3 (FRAXA) at the cytogenetic level, and both amplification of the (CGG)n repeat and hypermethylation of the CpG island in the 5' fragile X gene (FMR-1) at the molecular level. We have studied the FMR-1 gene of a patient with the fragile X phenotype but without cytogenetic expression of FRAXA, a (CGG)n repeat of normal length and an unmethylated CpG island. We find a single point mutation in FMR-1 resulting in an Ile367Asn substitution. This de novo mutation is absent in the patient's family and in 130 control X chromosomes, suggesting that the mutation causes the clinical abnormalities. Our results suggest that mutations in FMR-1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
- Published
- 1993
37. Genetic Overlaps in Mental Retardation, Autism and Schizophrenia
- Author
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Geert Vandeweyer, N. Van der Aa, Edwin Reyniers, Liesbeth Rooms, and R.F. Kooy
- Subjects
Genetics ,CNTNAP2 ,Schizophrenia ,Neurexin ,medicine ,Autism ,Disease ,Copy-number variation ,Biology ,medicine.disease ,Penetrance ,Gene - Abstract
Genetic aberrations are an important cause of mental retardation. De novo copy number variants (CNVs), either recurrent between unrelated individuals or unique have been identified as being causative for nearly 10% of cases and are, as a group, one of the leading causes of the disorder. Over the past two years, cohorts of patients with apparently distinct neuropsychiatric phenotypes such as autism and schizophrenia have also been analyzed for CNVs using genome wide detection methods and chromosomal abnormalities were detected in a significant amount of cases. Surprisingly, mutual disease related CNVs were found amongst these three seemingly completely distinct disorders, including in regions with the characteristics of a genomic disorder on chromosomes 1p21.1, 15q11–q13, 16p11.2 and 22q11.2. Moreover, two additional chromosomal regions encompassing the neurexin 1 and the CNTNAP2 gene were implicated in all three disorders, further stressing the importance of the neurexin pathway in the development of neuropsychiatric disease. Disease penetrance of each of these chromosomal abnormalities is never 100% and some abnormalities are occasionally found in seemingly unaffected carriers or healthy controls, indicating that additional environmental or genetic causes are necessary for the development of disease.
- Published
- 2010
38. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes
- Author
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Edwin Reyniers, Jessica Douglas, Anna Lindstrand, Howard R. Slater, Trijnie Dijkhuizen, Conny M. A. van Ravenswaaij-Arts, Catherine Nowak, Margaret P Adam, Devika Ganesamoorthy, Johanna Lundin, Jacqueline Schoumans, Bregje W.M. van Bon, Bert B.A. de Vries, David J. Amor, Carlos Cardoso, Martin B. Delatycki, Alison Yeung, Irene Stolte-Dijkstra, Birgit Borgström, D L Bruno, Christa Lese Martin, Nathalie Van der Aa, Anders Wallin, Geert Vandeweyer, Rolph Pfundt, Lena Thelin, R. Frank Kooy, Paul A. James, and Britt-Marie Anderlid
- Subjects
Male ,medicine.medical_specialty ,Candidate gene ,NUMBER VARIATION ,Adolescent ,IMPACT ,Lissencephaly ,Classical Lissencephalies and Subcortical Band Heterotopias ,Biology ,Craniofacial Abnormalities ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,PAFAH1B1 ,DIEKER-SYNDROME ,Segmental Duplications, Genomic ,Intellectual Disability ,Molecular genetics ,Genetics ,medicine ,Humans ,Child ,YWHAE ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Segmental duplication ,Chromosome Aberrations ,ALU REPEATS ,REARRANGEMENTS ,Brain ,Infant ,medicine.disease ,GENE ,Pedigree ,GENOMIC HYBRIDIZATION ,DELETIONS ,Phenotype ,Child, Preschool ,ARRAY ,Female ,Human genome ,Human medicine ,Chromosome Deletion ,Haploinsufficiency ,MENTAL-RETARDATION ,Chromosomes, Human, Pair 17 - Abstract
Contains fulltext : 88561.pdf (Publisher’s version ) (Closed access) BACKGROUND: Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. METHODS: Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. RESULTS: Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. CONCLUSIONS: The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations. 01 mei 2010
- Published
- 2010
39. Segregation of the fragile X mutation from an affected male to his normal daughter
- Author
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L Vits, Kristel De Boulle, Ben A. Oostra, Annemieke J.M.H. Verkerk, Patrick Willems, Edwin Reyniers, Olivia Beck, Bernadette Van Roy, and Jan E. Dumon
- Subjects
Adult ,Male ,medicine.medical_specialty ,Ichthyosis, X-Linked ,media_common.quotation_subject ,Germline mosaicism ,Biology ,Leukocytes ,Genetics ,medicine ,Humans ,Molecular Biology ,Gene ,Genetics (clinical) ,Arylsulfatases ,media_common ,Daughter ,Cytogenetics ,General Medicine ,Chromosome Fragility ,Middle Aged ,medicine.disease ,Pedigree ,Fragile X syndrome ,Child, Preschool ,Fragile X Syndrome ,Mutation ,Mutation (genetic algorithm) ,Female ,Steryl-Sulfatase ,Genomic imprinting - Abstract
We report here a family in which the fragile X mutation segregates from an affected grandfather through his normal daughter to an affected grandson. The grandson shows clinical and cytogenetic expression of fragile X syndrome due to a full mutation (large methylated insertion) in the fragile X gene (FMR-1). The mother shows a premutation (small unmethylated insertion) in her FMR-1 gene as the sole manifestation of the fragile X syndrome. The grandfather expresses the fragile X syndrome at the clinical and cytogenetic level, whereas he is mosaic for a methylated full mutation and an unmethylated premutation. The absence of expression of the fragile X mutation when transmitted through an expressing male might present further evidence for genomic imprinting of the FMR-1 gene. Alternatively, it is possible that the grandfather transmitted his premutation to his daughter due to germline mosaicism with both the premutation and the full mutation present in his sperm.
- Published
- 1992
40. Vitamin D-dependent rickets type II: report of a novel mutation in the vitamin D receptor gene
- Author
-
Yousef, Shafeghati, Nima, Momenin, Taher, Esfahani, Edwin, Reyniers, and Wim, Wuyts
- Subjects
Male ,Alopecia Areata ,Genetic Carrier Screening ,Siblings ,Glycine ,Infant ,Exons ,Iran ,Pedigree ,Consanguinity ,Child, Preschool ,Mutation ,Humans ,Receptors, Calcitriol ,Female ,Familial Hypophosphatemic Rickets ,Sequence Analysis - Abstract
Hereditary vitamin D-resistant rickets type or vitamin D-dependent rickets type II is a genetically determined and rare autosomal recessive disorder, most often caused by mutations in the vitamin D receptor gene. It usually presents with rachitic changes not responsive to vitamin D treatment and the circulating levels of 1,25 (OH)2 vitamin D-3 are elevated, differentiating it from vitamin D-dependent rickets type I. Alopecia capitis or alopecia totalis is seen in some families with vitamin D-dependent rickets type II. This is usually associated with a more severe phenotype. In this report, we present the clinical findings on a family which exhibited the typical clinical features of hereditary vitamin D-resistant rickets in two siblings. In addition, molecular analysis of the vitamin D receptor gene was performed by sequencing all coding exons. The cardinal findings in the index patient were alopecia totalis, renal tubular acidosis, mild generalized aminoaciduria, refractory rickets, high alkaline phosphatase, and hyperparathyroidism. Other routine biochemical tests were within normal limits, but 1+ glycine was detected in his urine. Skin biopsy results were compatible with alopecia areata. A previous child with similar phenotype was reported to be deceased at the age of 32 months. Mutation analysis of the vitamin D receptor gene by direct sequencing analysis of all coding exons showed a homozygous c.122GA(p.Cys41Tyr) variant in exon 2 with several arguments pointing to a pathogenic effect. We should be aware of this very rare disease whenever we see a patient with refractory rickets and alopecia.
- Published
- 2008
41. A de novo subtelomeric monosomy 11q (11q24.2-qter) and trisomy 20q (20q13.3-qter) in a girl with findings compatible with Jacobsen syndrome: case report and review
- Author
-
Jan Wauters, Edwin Reyniers, R. Frank Kooy, Rob van Luijk, Wim Wuyts, Liesbeth Rooms, Winnie Courtens, Stefaan Scheers, and Marek Wojciechowski
- Subjects
Adult ,Male ,Monosomy ,Chromosomes, Human, Pair 20 ,Trisomy ,Biology ,Pathology and Forensic Medicine ,Gene duplication ,medicine ,Humans ,Abnormalities, Multiple ,Jacobsen syndrome ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,medicine.diagnostic_test ,Psychomotor retardation ,Chromosomes, Human, Pair 11 ,Infant, Newborn ,Infant ,Chromosome Breakage ,General Medicine ,Nucleic acid amplification technique ,Syndrome ,Telomere ,medicine.disease ,Molecular biology ,Child, Preschool ,Karyotyping ,Pediatrics, Perinatology and Child Health ,Female ,Anatomy ,Chromosome breakage ,medicine.symptom ,Chromosome Deletion ,Nucleic Acid Amplification Techniques ,Fluorescence in situ hybridization - Abstract
We report on a 2-year-old dysmorphic girl with prenatal and postnatal growth deficiency, cardiopathy, left-sided hydronephrosis due to pyelourethral junction stenosis, frequent respiratory infections and psychomotor retardation, in whom a de novo unbalanced submicroscopic translocation (11q;20q) was detected by subtelomeric multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analyses. Additional fluorescence in situ hybridization studies with locus-specific BAC probes and analyses with microsatellite markers revealed that this translocation resulted in a paternal chromosome 11q terminal deletion of approximately 8.9 Mb and a subtelomeric 20q duplication of approximately 3.7 Mb. A subtelomeric 20q trisomy has only been reported in four cases so far. A subtelomeric 11q deletion has been clinically reported in 18 patients. We review the clinical phenotype of these patients. We suggest that patients with a subterminal (11q24.2/25-qter) deletion may present with features of the well-known phenotype of terminal 11q deletion or Jacobsen syndrome.
- Published
- 2007
42. Muscle pain as the only presenting symptom in a girl with dystrophinopathy
- Author
-
Jean Jacques Martin, Berten Ceulemans, Katrien Storm, Luc Callewaert, and Edwin Reyniers
- Subjects
Proband ,Adult ,Genetic Markers ,Male ,medicine.medical_specialty ,Weakness ,Pediatrics ,Adolescent ,Genotype ,media_common.quotation_subject ,DNA Mutational Analysis ,Cardiomyopathy ,Inheritance Patterns ,Pain ,Asymptomatic ,Dystrophin ,Sex Factors ,Developmental Neuroscience ,medicine ,Humans ,Girl ,Muscular dystrophy ,Age of Onset ,Muscle, Skeletal ,media_common ,business.industry ,medicine.disease ,Surgery ,Pedigree ,Muscular Dystrophy, Duchenne ,Neurology ,El Niño ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation ,Disease Progression ,Female ,Neurology (clinical) ,Age of onset ,medicine.symptom ,business ,Gene Deletion - Abstract
We present a family with dystrophinopathy in whom the proband is a female aged 4.5 years, who presented with exertional muscle pain without weakness. Familial analysis identified a maternal nephew of the proband who demonstrated a similar clinical picture, with asymptomatic cardiomyopathy. A DNA analysis revealed an in-frame deletion in the proximal part of domain II of the dystrophin gene. Extensive familial analysis indicated that the asymptomatic maternal grandfather transmitted the deletion. This is the first report of a young female patient with exertional muscle pain as the only early presenting symptom of dystrophinopathy.
- Published
- 2007
43. Diverse chromosome breakage mechanisms underlie subtelomeric rearrangements, a common cause of mental retardation
- Author
-
Edwin Reyniers, R. Frank Kooy, and Liesbeth Rooms
- Subjects
Genetics ,Breakpoint ,DNA Mutational Analysis ,Repetitive Sequences ,Chromosome ,Chromosomal translocation ,Chromosome Breakage ,Biology ,Telomere ,Subtelomere ,Translocation, Genetic ,Intellectual Disability ,Hum ,Humans ,Nucleic Acid Conformation ,Chromosome breakage ,Genetics (clinical) ,Gene Deletion - Abstract
Subtelomeric rearrangements are an important cause of both isolated and familial idiopathic mental retardation. A variety of different rearrangements such as pure truncations, unbalanced translocations, interstitial deletions, and inverted duplications have been detected throughout various screening studies. The cause of these aberrations is poorly understood as only few of the breakpoints have been determined and studied. We molecularly characterized the breakpoints of three rearrangements including a 1p subtelomeric deletion, a 1q subtelomeric deletion, and an unbalanced translocation between chromosomes 11q and 20q; we propose that diverse chromosome breakage mechanisms underlie subtelomeric rearrangements. The breakpoint sequences suggest that unusual non-B-DNA structures including triplex, tetraplex, and hairpin structures may be involved. In addition, we saw that the seemingly pure truncations of chromosomes 1p and 1q were in fact more complex rearrangements as highly repetitive sequences were joined to the chromosome end at the site of breakage. Hum Mutat 28(2), 177–182, 2007. © 2006 Wiley-Liss, Inc.
- Published
- 2007
44. TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions
- Author
-
Zsuzsanna Callaerts-Vegh, R. Frank Kooy, Irwin Davidson, Edwin Reyniers, Rob van Luijk, Winnie Courtens, Jan Wauters, Stefaan Scheers, Liesbeth Rooms, Rudi D'Hooge, Leen Van Aerschot, Gabrielle Mengus, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Candidate gene ,Microcephaly ,Monozygotic twin ,MESH: TATA-Box Binding Protein ,Anxiety ,Mice ,MESH: Mental Retardation ,MESH: Animals ,Genetics (clinical) ,Genetics ,0303 health sciences ,030305 genetics & heredity ,Subtelomere ,MESH: Memory Disorders ,Null allele ,Pedigree ,Chemistry ,Chromosomes, Human, Pair 6 ,Female ,MESH: Twins, Monozygotic ,Chromosome Deletion ,MESH: Abnormalities, Multiple ,MESH: Chromosomes, Human, Pair 6 ,Adolescent ,MESH: Pedigree ,MESH: Chromosome Deletion ,Biology ,03 medical and health sciences ,Gene mapping ,Intellectual Disability ,medicine ,Diseases in Twins ,Animals ,Humans ,Abnormalities, Multiple ,Gene ,MESH: Mice ,030304 developmental biology ,MESH: Adolescent ,Memory Disorders ,MESH: Humans ,MESH: Anxiety ,Breakpoint ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Twins, Monozygotic ,medicine.disease ,TATA-Box Binding Protein ,MESH: Male ,Human medicine ,MESH: Diseases in Twins ,MESH: Female - Abstract
International audience; Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development.
- Published
- 2006
45. A de novo subterminal trisomy 10p and monosomy 18q in a girl with MCA/MR: case report and review
- Author
-
R. Frank Kooy, Rob van Luijk, Stefaan Scheers, Liesbeth Rooms, Wim Wuyts, Winnie Courtens, Jan Wauters, Berten Ceulemans, and Edwin Reyniers
- Subjects
Proband ,Monosomy ,Aneuploidy ,Chromosomal translocation ,Trisomy ,Biology ,Translocation, Genetic ,Chromosome 18 ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Multiplex ligation-dependent probe amplification ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,Psychomotor retardation ,Chromosomes, Human, Pair 10 ,General Medicine ,medicine.disease ,Molecular biology ,Child, Preschool ,Female ,medicine.symptom ,Chromosome Deletion ,Chromosomes, Human, Pair 18 ,Nucleic Acid Amplification Techniques ,Microsatellite Repeats - Abstract
We report on a 3-year-old girl with psychomotor retardation, cardiopathy, strabismus, umbilical hernia, and facial dysmorphism in whom a de novo unbalanced submicroscopic translocation (10p;18q) was found by MLPA (Multiplex Ligation dependent Probe Amplification) and FISH analyses. Additional FISH studies with locus specific RP11 BAC probes and analyses with microsatellites revealed that the translocation resulted in a deletion estimated between 6 and 9 Mb on the maternal chromosome 18 and a subtelomeric 10p duplication of approximately 6.9 Mb. The proband's karyotype is 46,XX.ish der(18) t(10;18)(18pter--18q23:10p15 --10pter). A subterminal duplication of 10p, as well as a subterminal deletion of 18q have been rarely reported so far. The clinical phenotype of this patient is reviewed and discussed.
- Published
- 2006
46. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism
- Author
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Ad Geurts van Kessel, Edwin Reyniers, Jacqueline Schoumans, Erik A. Sistermans, Britt-Marie Anderlid, R. Frank Kooy, Regina Regan, Albert Schinzel, David A. Koolen, Alessandra Baumer, Samantha J. L. Knight, Rolph Pfundt, Lisenka E.L.M. Vissers, Bert B.A. de Vries, Joris A. Veltman, Nine V A M Knoers, Corrado Romano, Marco Fichera, Han G. Brunner, Nicole de Leeuw, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), University of Zurich, and de Vries, Bert B A
- Subjects
Health aging / healthy living [IGMD 5] ,Genetics and epigenetic pathways of disease [NCMLS 6] ,Koolen De Vries syndrome ,10039 Institute of Medical Genetics ,Membrane transport and intracellular motility [NCMLS 5] ,610 Medicine & health ,Mentally retarded ,Biology ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,1311 Genetics ,Translational research [ONCOL 3] ,Inversion polymorphism ,Genetics ,medicine ,Gene ,Renal disorder [IGMD 9] ,Hereditary cancer and cancer-related syndromes [ONCOL 1] ,Chromosome ,medicine.disease ,17q21.31 microdeletion syndrome ,Hypotonia ,Genetic defects of metabolism [UMCN 5.1] ,Cohort ,570 Life sciences ,biology ,medicine.symptom ,Functional Neurogenomics [DCN 2] - Abstract
Contains fulltext : 49578.pdf (Publisher’s version ) (Closed access) Submicroscopic genomic copy number changes have been identified only recently as an important cause of mental retardation. We describe the detection of three interstitial, overlapping 17q21.31 microdeletions in a cohort of 1,200 mentally retarded individuals associated with a clearly recognizable clinical phenotype of mental retardation, hypotonia and a characteristic face. The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism.
- Published
- 2006
47. Clinical report of a pure subtelomeric 1qter deletion in a boy with mental retardation and multiple anomalies adds further evidence for a specific phenotype
- Author
-
Edwin Reyniers, Annick Laridon, Rob van Luijk, Jan Wauters, Yolande van Bever, Stefaan Scheers, Liesbeth Rooms, and R. Frank Kooy
- Subjects
Male ,Biology ,Corpus callosum ,Epilepsy ,Gene mapping ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Genetics (clinical) ,Growth Disorders ,Progressive microcephaly ,Breakpoint ,Chromosome ,Infant ,Telomere ,medicine.disease ,Subtelomere ,Developmental disorder ,Phenotype ,Chromosomes, Human, Pair 1 ,Child, Preschool ,Karyotyping ,Microcephaly ,Chromosome Deletion - Abstract
Deletions of the 1q telomere have been reported in several studies screening for subtelomeric rearrangements. However, an adequate clinical description is available from only a few patients. We provide a clinical description of a patient with a subtelomeric deletion of chromosome 1q, previously detected by us in a screening study. Comparison of the clinical presentation of our patient with rare cases reported previously provides further evidence for a specific phenotype of 1q patients, including mental retardation, growth retardation, sometimes with prenatal onset, progressive microcephaly, seizures, hand and foot abnormalities and a variety of midline defects, including corpus callosum, cardiac, genital and gastro-esophageal abnormalities. This clinical presentation is reminiscent of that of patients with larger, microscopically visible deletions of chromosome 1q (>3 Mb) characterized by growth and mental retardation, coarse faces with thin upper lip, epilepsy, and variable other anomalies. In addition, the breakpoint region was mapped to a 26 kb region within the RGS7 gene. Among the 17 known genes in the candidate region, are zinc-finger genes. Other members of this gene family have been implicated in different forms of mental retardation.
- Published
- 2005
48. Somatic and gonadal mosaicism in Hutchinson-Gilford progeria
- Author
-
Giuseppe Novelli, Martine Biervliet, Maria Rosaria D'Apice, Katrien Storm, Wim Wuyts, Edwin Reyniers, Surgical clinical sciences, and Clinical sciences
- Subjects
Male ,Hutchinson-Gilford progeria ,LMNA ,Mosaicism ,congenital, hereditary, and neonatal diseases and abnormalities ,Child, preschool ,Somatic cell ,DNA Mutational Analysis ,Germline mosaicism ,Biology ,medicine.disease_cause ,Germline mutation ,Progeria ,Genetics ,medicine ,Humans ,Point Mutation ,Allele ,Genetics (clinical) ,Germ-Line Mutation ,Family Health ,Mutation ,Case reports ,integumentary system ,Base Sequence ,Point mutation ,Research Support, Non-U.S. Gov't ,nutritional and metabolic diseases ,medicine.disease ,Lamin Type A ,Pedigree ,Settore MED/03 - Genetica Medica ,embryonic structures ,Female ,Human medicine - Abstract
We have studied a patient with Hutchinson-Gilford progeria (HGP). Sequence analysis of the LMNA gene demonstrated the presence of a c.1824 C > T (p.G608G) mutation, activating a cryptic splice donor site and leading to the formation of a truncated Lamin A protein. All molecularly characterized autosomal dominant HGP cases described so far result from de novo LMNA mutations, mostly originating on the paternal allele and are often linked with advanced paternal age. However, in our patient, the mutation was transmitted by the mother who showed somatic and germline mosaicism without HGP manifestations. (c) 2005 Wiley-Liss, Inc.
- Published
- 2005
49. Myopathy and phosphorylase kinase deficiency caused by a mutation in the **PHKA1** gene
- Author
-
Jean-Jacques Martin, Katrien Storm, Thierry de Barsy, Wim Wuyts, Chantal Ceuterick, and Edwin Reyniers
- Subjects
Adult ,Male ,Phosphorylase Kinase ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,Frameshift mutation ,Muscular Diseases ,Genetics ,medicine ,Humans ,Phosphorylase kinase ,Myopathy ,Frameshift Mutation ,Muscle, Skeletal ,Gene ,Genetics (clinical) ,G alpha subunit ,chemistry.chemical_classification ,Mutation ,Chromosomes, Human, X ,Chromosome ,DNA ,Molecular biology ,Microscopy, Electron ,Protein Subunits ,Enzyme ,chemistry ,medicine.symptom - Abstract
Phosphorylase kinase (PhK) deficiency is the underlying cause of variable clinical symptoms depending on the tissues involved. Until today, only a few cases of myopathy associated with muscle PhK deficiency caused by a mutation in the gene encoding the alpha subunit of phosphorylase kinase (PHKA1) have been reported. We describe a male patient with myopathy and absent muscle PhK activity caused by a frameshift mutation in the gene encoding the alpha subunit of PhK on chromosome Xq12-q13.
- Published
- 2005
50. Screening for subtelomeric rearrangements using genetic markers in 70 patients with unexplained mental retardation
- Author
-
Edwin Reyniers, R. Frank Kooy, Rob van Luijk, Jan Wauters, Stefaan Scheers, and Liesbeth Rooms
- Subjects
Genetics ,Chromosome Aberrations ,Genetic Markers ,Polymorphism, Genetic ,medicine.diagnostic_test ,Chromosome ,Biology ,Telomere ,Subtelomere ,Genetic determinism ,Genetic marker ,Intellectual Disability ,Genotype ,medicine ,Microsatellite ,Humans ,Genetic Testing ,Genotyping ,Fluorescence in situ hybridization ,Microsatellite Repeats - Abstract
Cryptic unbalanced rearrangements involving chromosome ends are a significant cause of idiopathic mental retardation. The most frequently used technique to screen for these subtle rearrangements is Multiprobe fluorescence in situ hybridization (FISH). As this is a labor-intensive technique, we used microsatellite genotyping to detect possible subtelomeric rearrangements in a study population. Out of the 70 patients we screened, three chromosomal rearrangements were detected: a deletion of marker D2S2986, a deletion of marker D7S594 and a deletion of marker D19S424. However, none of these aberrations appeared to be disease causing.
- Published
- 2004
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