Tjitske Kleefstra

Summary

Affiliation: Radboud University Nijmegen Medical Centre
Country: The Netherlands

Publications

  1. ncbi request reprint MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics
    Tjitske Kleefstra
    Department of Human Genetics, University Medical Centre St Radboud, PO Box 9101, Nijmegen 6500 HB, The Netherlands
    Eur J Hum Genet 12:24-8. 2004
  2. ncbi request reprint Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1)
    T Kleefstra
    Department of Human Genetics, University Medical Center, Nijmegen, The Netherlands
    Clin Genet 66:318-26. 2004
  3. ncbi request reprint Interstitial 2.2 Mb deletion at 9q34 in a patient with mental retardation but without classical features of the 9q subtelomeric deletion syndrome
    Tjitske Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands
    Am J Med Genet A 140:618-23. 2006
  4. pmc Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome
    Tjitske Kleefstra
    Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB Nijmegen, The Netherlands
    Am J Hum Genet 79:370-7. 2006
  5. doi request reprint Phenotypic spectrum of 20 novel patients with molecularly defined supernumerary marker chromosomes 15 and a review of the literature
    Tjitske Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Med Genet A 152:2221-9. 2010
  6. doi request reprint Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
    T Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    J Med Genet 46:598-606. 2009
  7. doi request reprint Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies
    Marjolein H Willemsen
    849 Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    Eur J Med Genet 55:586-98. 2012
  8. ncbi request reprint Low frequency of MECP2 mutations in mentally retarded males
    Helger G Yntema
    Department of Human Genetics, University Medical Center, Nijmegen, The Netherlands
    Eur J Hum Genet 10:487-90. 2002
  9. doi request reprint Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation
    Dorien Lugtenberg
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Med Genet A 152:638-45. 2010
  10. pmc Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome
    Marjolein H Willemsen
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands
    Eur J Hum Genet 18:429-35. 2010

Detail Information

Publications45

  1. ncbi request reprint MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics
    Tjitske Kleefstra
    Department of Human Genetics, University Medical Centre St Radboud, PO Box 9101, Nijmegen 6500 HB, The Netherlands
    Eur J Hum Genet 12:24-8. 2004
    ..In the remaining patients with unexplained mental retardation, additional clinical features should determine whether analysis of MECP2 is indicated...
  2. ncbi request reprint Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1)
    T Kleefstra
    Department of Human Genetics, University Medical Center, Nijmegen, The Netherlands
    Clin Genet 66:318-26. 2004
    ..These observations contribute to the phenotypic knowledge of patients with PQBP1 mutations and make this XLMR syndrome well recognizable to clinicians...
  3. ncbi request reprint Interstitial 2.2 Mb deletion at 9q34 in a patient with mental retardation but without classical features of the 9q subtelomeric deletion syndrome
    Tjitske Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands
    Am J Med Genet A 140:618-23. 2006
    ..Moreover, it confirms the importance of the Eu-HMTase1 gene as the major causative factor of the classical 9qter syndrome phenotype...
  4. pmc Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome
    Tjitske Kleefstra
    Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB Nijmegen, The Netherlands
    Am J Hum Genet 79:370-7. 2006
    ..These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome...
  5. doi request reprint Phenotypic spectrum of 20 novel patients with molecularly defined supernumerary marker chromosomes 15 and a review of the literature
    Tjitske Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Med Genet A 152:2221-9. 2010
    ..Motor and speech development varied extensively among the patients. An association was found between positive seizure history and degree of intellectual disability...
  6. doi request reprint Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype
    T Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    J Med Genet 46:598-606. 2009
    ..So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far...
  7. doi request reprint Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies
    Marjolein H Willemsen
    849 Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    Eur J Med Genet 55:586-98. 2012
    ..The prevalence of X-chromosome copy number variations in this cohort was 57/4407 (∼1.3%), of which 15 (0.3%) were interpreted as (likely) pathogenic...
  8. ncbi request reprint Low frequency of MECP2 mutations in mentally retarded males
    Helger G Yntema
    Department of Human Genetics, University Medical Center, Nijmegen, The Netherlands
    Eur J Hum Genet 10:487-90. 2002
    ..The true frequency of MECP2 mutations in the mentally retarded has probably been overestimated. Based on our data, the frequency of MECP2 mutations in mentally retarded males is 0.2% (1/475)...
  9. doi request reprint Recurrent deletion of ZNF630 at Xp11.23 is not associated with mental retardation
    Dorien Lugtenberg
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Med Genet A 152:638-45. 2010
    ..9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation...
  10. pmc Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome
    Marjolein H Willemsen
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands
    Eur J Hum Genet 18:429-35. 2010
    ..3 microdeletion syndrome might uncover other mutations in one or both of these genes...
  11. ncbi request reprint Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium
    Arjan P M de Brouwer
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Hum Mutat 28:207-8. 2007
    ..Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers...
  12. pmc Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy
    Dorien Lugtenberg
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Eur J Hum Genet 17:444-53. 2009
    ..We propose to implement DNA copy number testing for MECP2 in the current diagnostic testing in all males with moderate to severe mental retardation accompanied by (progressive) neurological symptoms...
  13. doi request reprint Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing
    Janneke H M Schuurs-Hoeijmakers
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    J Med Genet 50:802-11. 2013
    ..Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown...
  14. doi request reprint Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability
    Marjolein H Willemsen
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    J Med Genet 48:810-8. 2011
    ..Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions...
  15. doi request reprint Diagnostic exome sequencing in persons with severe intellectual disability
    Joep de Ligt
    Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    N Engl J Med 367:1921-9. 2012
    ..The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity...
  16. pmc Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome
    T Kleefstra
    Department of Human Genetics, University Medical Centre St Radboud, Nijmegen, The Netherlands
    J Med Genet 42:299-306. 2005
    ..The minimum critical region responsible for this 9q subtelomeric deletion syndrome (9q-) is approximately 1.2 Mb and encompasses at least 14 genes...
  17. pmc A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype
    Zafar Iqbal
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Eur J Hum Genet 21:844-9. 2013
    ..Our results show that the clinical spectrum of DPAGT1-CDG is much broader than appreciated so far. ..
  18. pmc Mutations in MED12 cause X-linked Ohdo syndrome
    Anneke T Vulto-van Silfhout
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Hum Genet 92:401-6. 2013
    ..Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome...
  19. doi request reprint Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects
    Marjolein H Willemsen
    Radboud University Nijmegen Medical Centre, Department of Human Genetics, Nijmegen, The Netherlands
    J Med Genet 49:179-83. 2012
    ..Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome...
  20. doi request reprint UBE2A deficiency syndrome: Mild to severe intellectual disability accompanied by seizures, absent speech, urogenital, and skin anomalies in male patients
    Nicole de Leeuw
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Med Genet A 152:3084-90. 2010
    ..Facial dysmorphisms include a wide face, a depressed nasal bridge, a large mouth with downturned corners, thin vermilion, and a short, broad neck...
  21. doi request reprint Further molecular and clinical delineation of the Wisconsin syndrome phenotype associated with interstitial 3q24q25 deletions
    Marjolein H Willemsen
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Med Genet A 155:106-12. 2011
    ....
  22. doi request reprint Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome
    Willy M Nillesen
    Department of Human Genetics, RUNMC, Nijmegen, The Netherlands
    Hum Mutat 32:853-9. 2011
    ..These results have important implications for the genetic screening of KS and for studies of the functional significance of EHMT1...
  23. pmc ZNF674: a new kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation
    Dorien Lugtenberg
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Am J Hum Genet 78:265-78. 2006
    ..Identification of ZNF674 as the third XLMR gene in this cluster may indicate a common role for these zinc-finger genes that is crucial to human cognitive functioning...
  24. doi request reprint GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila
    Marjolein H Willemsen
    Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
    J Med Genet 50:507-14. 2013
    ..We recently identified two de novo loss-of-function mutations in GATAD2B by whole exome sequencing in two unrelated individuals with severe intellectual disability...
  25. pmc Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability
    Tjitske Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands
    Am J Hum Genet 91:73-82. 2012
    ..We propose a highly conserved epigenetic network that underlies cognition in health and disease. This network should allow the design of strategies to treat the growing group of ID pathologies that are caused by epigenetic defects...
  26. doi request reprint Clinical and molecular characterization of two patients with a 6.75 Mb overlapping deletion in 8p12p21 with two candidate loci for congenital heart defects
    Marjolein H Willemsen
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Eur J Med Genet 52:134-9. 2009
    ..The aforementioned clinical characteristics should be considered in the care of patients with a proximal interstitial 8p12p21 deletion...
  27. pmc Homozygosity mapping in outbred families with mental retardation
    Janneke H M Schuurs-Hoeijmakers
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Eur J Hum Genet 19:597-601. 2011
    ..9 Mb (98 genes) in common with the 5.4 Mb MRT11 locus (195 genes). These data support that homozygosity mapping in outbred families may contribute to identification of novel AR-MR genes...
  28. doi request reprint Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome
    Monique C M Balemans
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
    Hum Mol Genet 22:852-66. 2013
    ..These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS...
  29. ncbi request reprint Pure subtelomeric microduplications as a cause of mental retardation
    E M Ruiter
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
    Clin Genet 72:362-8. 2007
    ..5%. Our study shows that subtelomeric microduplications are an infrequent cause of MR and that additional clinical and family studies are required to assess their clinical significance...
  30. pmc Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway
    Tjitske Kleefstra
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Eur J Hum Genet 19:138-44. 2011
    ..We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction...
  31. ncbi request reprint Identification of an unbalanced cryptic translocation between the chromosomes 8 and 13 in two sisters with mild mental retardation accompanied by mild dysmorphic features
    T Kleefstra
    Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands
    Eur J Hum Genet 8:637-40. 2000
    ..3;q34)) was detected on routine cytogenetic investigation followed by additional FISH studies. The translocation originated from the mother...
  32. ncbi request reprint X-linked mental retardation: further lumping, splitting and emerging phenotypes
    T Kleefstra
    Department of Human Genetics, Radboud University Medical Center Nijmegen, The Netherlands
    Clin Genet 67:451-67. 2005
    ..Therefore, in this review, focus has been given on the clinical data and on phenotype-genotype correlations for those genes implicated in both non-syndromic and syndromic XLMR...
  33. pmc Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome
    B W M Van Bon
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
    J Med Genet 46:511-23. 2009
    ..Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy...
  34. ncbi request reprint A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy
    Arjan Pm de Brouwer
    1 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 2 Institute of Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands
    Eur J Hum Genet . 2013
    ..In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.European Journal of Human Genetics advance online publication, 31 July 2013; doi:10.1038/ejhg.2013.169...
  35. doi request reprint 3-Methylglutaconic aciduria--lessons from 50 genes and 977 patients
    Saskia B Wortmann
    Nijmegen Center for Mitochondrial Disorders NCMD at the Department of Pediatrics and the Institute of Genetic and Metabolic Disease IGMD, Radboud University Medical Centre, P O Box 9101, 6500 HB, Nijmegen, The Netherlands
    J Inherit Metab Dis 36:913-21. 2013
    ..These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature...
  36. pmc OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin
    Karlien L M Coene
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands
    Am J Hum Genet 85:465-81. 2009
    ..These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS...
  37. pmc Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH
    D Lugtenberg
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB Nijmegen, The Netherlands
    J Med Genet 43:362-70. 2006
    ..These results confirm the power of array CGH as a diagnostic tool, but also emphasise the necessity to perform proper validation experiments by an independent technique...
  38. ncbi request reprint De novo MECP2 frameshift mutation in a boy with moderate mental retardation, obesity and gynaecomastia
    T Kleefstra
    Department of Human Genetics, University Medical Center, St Radboud, Nijmegen, The Netherlands
    Clin Genet 61:359-62. 2002
    ..This report contributes to the phenotypic knowledge of male patients with MECP2 mutations. Moreover, this is the first reported male case of a de novo MECP2 mutation...
  39. pmc Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation
    Lars Riff Jensen
    Max Planck Institute for Molecular Genetics, Berlin, Germany
    Am J Hum Genet 76:227-36. 2005
    ..Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function...
  40. pmc High prevalence of SLC6A8 deficiency in X-linked mental retardation
    Efraim H Rosenberg
    Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands
    Am J Hum Genet 75:97-105. 2004
    ..M560V). Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome...
  41. ncbi request reprint Novel JARID1C/SMCX mutations in patients with X-linked mental retardation
    Andreas Tzschach
    Max Planck Institute for Molecular Genetics, Berlin, Germany
    Hum Mutat 27:389. 2006
    ..In contrast to other XLMR genes in which mutations were found only in single or very few families, JARID1C appears to be one of the more frequently mutated genes in this disorder...
  42. ncbi request reprint The chromosome 9q subtelomere deletion syndrome
    Douglas R Stewart
    National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bldg 49, Room 4A62, Bethesda, MD 20892, USA
    Am J Med Genet C Semin Med Genet 145:383-92. 2007
    ..EHMT1 is another example in the growing list of genes responsible for brain development that appear to play a role in chromatin remodeling. Published 2007 Wiley-Liss, Inc...
  43. ncbi request reprint In-frame deletion in MECP2 causes mild nonspecific mental retardation
    Helger G Yntema
    Am J Med Genet 107:81-3. 2002
  44. ncbi request reprint Localization of a gene for nonspecific X-linked mental retardation (MRX 76) to Xp22.3-Xp21.3
    Tjitske Kleefstra
    Am J Med Genet 110:410-1. 2002
  45. ncbi request reprint Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application
    Efraim H Rosenberg
    Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands
    Hum Mutat 28:890-6. 2007
    ..Pro554Leu) are pathogenic mutations and four variants (p.Lys4Arg, p.Gly26Arg, p.Met560Val, and p.Val629Ile) are nonpathogenic. The present study provides an improved diagnostic tool to classify sequence variants of unknown significance...