Thomy de Ravel

Publications (33)237.23 Total impact

• Article: Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12.

  Christophe Goubau, Koen Devriendt, Nathalie Van der Aa, An Crepel, Dagmar Wieczorek, Tjitske Kleefstra, Marjolein H Willemsen, Anita Rauch, Andreas Tzschach, Thomy de Ravel, Peter Leemans, Chris Van Geet, Gunnar Buyse, Kathleen Freson
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  ABSTRACT: The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.European Journal of Human Genetics advance online publication, 1 May 2013; doi:10.1038/ejhg.2013.86.
  European journal of human genetics: EJHG 05/2013; · 3.56 Impact Factor
• Article: Peculiar fundus abnormalities and pathognomonic electrophysiological findings in a 14-month-old boy with NR2E3 mutations.

  Catherine Cassiman, Werner Spileers, Elfride De Baere, Thomy de Ravel, Ingele Casteels
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  ABSTRACT: Enhanced S-cone syndrome is a rare, slowly progressive autosomal recessively inherited retinal degeneration related to mutations in the NR2E3 gene. Patients often present with night blindness, visual loss and visual field abnormalities. Patients with enhanced S-cone syndrome exhibit a variable clinical phenotype associated with various degrees of pigmentary changes and foveal schisis. We report a 14-month-old boy with an unusual funduscopic appearance. The diagnosis of enhanced S-cone syndrome was suggested by the uniquely abnormal electroretinographic pattern and was confirmed by the finding of homozygous NR2E3 mutations.
  Ophthalmic Genetics 10/2012; · 0.93 Impact Factor
• Source

  Available from: Ann Swillen

  Article: Social phenotypes in genetic syndromes.

  Ann Swillen, Thomy de Ravel, Chris Oliver
  Journal of Intellectual Disability Research 10/2012; 56(10):919-21. · 1.88 Impact Factor
• Article: Fetal pyelectasis and corkscrew-shaped ureters: an association observed in postmortem fetal imaging studies of osteochondrodysplasia and trisomy 21.

  Kenneth Carels, Luc De Catte, Philippe Moerman, Thomy de Ravel, Raymond Oyen, Jan Deprest, Filip Claus
  Prenatal Diagnosis 04/2012; 32(7):698-9. · 2.11 Impact Factor
• Article: Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors.

  Eline Beert, Hilde Brems, Bruno Daniëls, Ivo De Wever, Frank Van Calenbergh, Joseph Schoenaers, Maria Debiec-Rychter, Olivier Gevaert, Thomas De Raedt, Annick Van Den Bruel, Thomy de Ravel, Karen Cichowski, Lan Kluwe, Victor Mautner, Raf Sciot, Eric Legius
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  ABSTRACT: Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.
  Genes Chromosomes and Cancer 12/2011; 50(12):1021-32. · 3.31 Impact Factor
• Source

  Available from: Hubert J Smeets

  Article: MLL2 mutation spectrum in 45 patients with Kabuki syndrome.

  Aimée D C Paulussen, Alexander P A Stegmann, Marinus J Blok, Demis Tserpelis, Crool Posma-Velter, Yvonne Detisch, Eric E J G L Smeets, Annemieke Wagemans, Jaap J P Schrander, Marie-José H van den Boogaard, [......], Grazia M Mancini, Marja W Wessels, Raoul C M Hennekam, Maaike Vreeburg, Joep Geraedts, Thomy de Ravel, Jean-Pierre Fryns, Hubert J Smeets, Koenraad Devriendt, Constance T R M Schrander-Stumpel
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  ABSTRACT: Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS.
  Human Mutation 02/2011; 32(2):E2018-25. · 5.69 Impact Factor
• Article: High frequency of submicroscopic chromosomal deletions in patients with idiopathic congenital eye malformations.

  Irina Balikova, Thomy de Ravel, Carmen Ayuso, Bernard Thienpont, Ingele Casteels, Cristina Villaverde, Koenraad Devriendt, Jean-Pierre Fryns, Joris Robert Vermeesch
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  ABSTRACT: The purpose of this study was to evaluate the clinical usefulness of the array comparative genomic hybridization technique for the genetic analysis of patients with congenital ocular malformations. Laboratory investigation. This was a multicenter study. Samples were collected from 37 patients with negative results for the routine diagnostic work-up, including normal karyotype and mutation analysis of appropriate genes. Samples from both parents also were tested. High-resolution genome-wide Agilent 244K oligoarray (Agilent Technologies) was applied. Confirmation of the results was obtained with independent techniques. Causal deletions were identified in 5 (13%) patients, affecting OTX2, FOXC1 and VPS13B (COH1), the downstream regulatory region of PAX6, and a 1,5 Megabases de novo deletion on chromosome 16. This high frequency of causal submicroscopic chromosomal aberrations in patients with congenital ocular malformation warrants implementation of array comparative genomic hybridization in the diagnostic work-up of these patients. Moreover, this screening technique broadens the phenotypic and mutational spectrum associated with genes known to cause congenital ocular malformation.
  American journal of ophthalmology 02/2011; 151(6):1087-1094.e45. · 3.83 Impact Factor
• Article: Diffuse choroidal atrophy in a boy with klinefelter syndrome.

  Sofie Verstraeten, Nele Jaenen, Werner Spileers, Thomy de Ravel, Ingele Casteels
  Journal of Pediatric Ophthalmology & Strabismus 01/2011; 48(1):64. · 0.63 Impact Factor
• Article: Postmortem fetal imaging of a metabolic pluricystic kidney disease.

  Filip Claus, An Hindryckx, Thomy de Ravel, Inga Sandaite, Luc De Catte, Philippe Moerman
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  ABSTRACT: Postmortem magnetic resonance images of a pluricystic kidney disease due to an inborn error of the fatty acid metabolism are presented.
  Fetal Diagnosis and Therapy 01/2011; 30(4):317-8. · 1.05 Impact Factor
• Source

  Available from: Joris Vermeesch

  Article: 2q31.1 microdeletion syndrome: redefining the associated clinical phenotype.

  Boyan Dimitrov, Irina Balikova, Thomy de Ravel, Hilde Van Esch, Maryse De Smedt, Emiel Baten, Joris Robert Vermeesch, Irena Bradinova, Emil Simeonov, Koen Devriendt, Jean-Pierre Fryns, Philippe Debeer
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  ABSTRACT: The clinical phenotype of the chromosome 2q31 deletion syndrome consists of limb anomalies ranging from monodactylous ectrodactyly, brachydactyly and syndactyly to camptodactyly. Additional internal organ anomalies-for example, heart defects, ocular anomalies-may be present. Hemizygosity for HOXD13 and EVX2 genes was thought to cause the observed skeletal defects. Recently, based on the phenotype of patients with overlapping 2q31 interstitial deletions, a new SHFM5 locus was proposed, proximal to the HOXD cluster, between EVX2 and marker D2S294. DLX1 and DLX2 haploinsufficiency was suggested as the most plausible explanation for the observed SHFM-like limb anomalies in these cases. Five unique, interstitial 2q31 deletion patients were selected to further characterise the 2q31 region and to establish a genotype/phenotype correlation map. The size of the deletions was delineated with a chromosome 2 specific tiling path bacterial artificial chromosome (BAC) array. The clinical and molecular data for this group of patients were compared to others in the literature. A common locus for the observed skeletal anomalies, including the HOXD genes and surrounding regulatory sequences, was delineated. These results correlate with recently published studies in animal models. In addition, a critical region for the facial gestalt of the 2q31.1 microdeletion syndrome was delineated. These results reinforce the hypothesis that the variable skeletal phenotype in 2q31 deletion patients is a result of hemizygosity for the HOXD genes and that the 2q31.1 microdeletion syndrome is a well defined and clinically recognisable phenotype.
  Journal of Medical Genetics 11/2010; 48(2):98-104. · 6.36 Impact Factor
• Article: Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations.

  Barbara D'haene, Françoise Meire, Ilse Claerhout, Hester Y Kroes, Astrid Plomp, Yvonne H Arens, Thomy de Ravel, Ingele Casteels, Sarah De Jaegere, Sally Hooghe, [......], Hermine E Veenstra-Knol, Rogier A Oldenburg, Jacques Giltay, Johanna B G M Verheij, Jan-Tjeerd de Faber, Björn Menten, Anne De Paepe, Philippe Kestelyn, Bart P Leroy, Elfride De Baere
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  ABSTRACT: Anterior segment dysgenesis (ASD) comprises a heterogeneous group of developmental abnormalities that affect several structures of the anterior segment of the eye. The main purpose of this study was to assess the proportion of FOXC1 and PITX2 mutations and copy number changes in 80 probands with ASD. The patients were examined for FOXC1 and PITX2 copy number changes and mutations using MLPA (multiplex ligation-dependent probe amplification) and direct sequencing. Subsequently, the identified copy number changes were fine-mapped using high-resolution microarrays. In the remaining mutation-negative patients, sequencing of the FOXC1 andPITX2 3' untranslated regions (UTRs) and three other candidate genes (P32, PDP2, and FOXC2) was performed. Thirteen FOXC1 and eight PITX2 mutations were identified, accounting for 26% (21/80) of the cases. In addition, six FOXC1 and five PITX2 deletions were found, explaining 14% (11/80) of the cases. The smallest FOXC1 and PITX2 deletions were 5.4 and 1.6 kb in size, respectively. Six patients carrying FOXC1 deletions presented with variable extraocular phenotypic features such as hearing defects (in 4/6) and mental retardation (in 2/6). No further genetic defects were found in the remaining mutation-negative patients. FOXC1 and PITX2 genetic defects explain 40% of our large ASD cohort. The current spectrum of intragenic FOXC1 and PITX2 mutations was extended considerably, the identified copy number changes were fine mapped, the smallest FOXC1 and PITX2 deletions reported so far were identified, and the need for dedicated copy number screening of the FOXC1 and PITX2 genomic landscape was emphasized. This study is unique in that sequence and copy number changes were screened simultaneously in both genes.
  Investigative ophthalmology & visual science 09/2010; 52(1):324-33. · 3.43 Impact Factor
• Source

  Available from: Sarah De Jaegere

  Article: Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290‐related phenotypes

  Frauke Coppieters, Ingele Casteels, Françoise Meire, Sarah De Jaegere, Sally Hooghe, Nicole van Regemorter, Hilde Van Esch, Aušra Matulevičienė, Luis Nunes, Valérie Meersschaut, Sophie Walraedt, Lieve Standaert, Paul Coucke, Heidi Hoeben, Hester Y. Kroes, Johan Vande Walle, Thomy de Ravel, Bart P. Leroy, Elfride De Baere
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  ABSTRACT: Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease. © 2010 Wiley-Liss, Inc.
  Human Mutation 08/2010; 31(10):E1709 - E1766. · 5.69 Impact Factor
• Article: Deletion and point mutations of PTHLH cause brachydactyly type E.

  Eva Klopocki, Bianca P Hennig, Katarina Dathe, Randi Koll, Thomy de Ravel, Emiel Baten, Eveline Blom, Yves Gillerot, Johannes F W Weigel, Gabriele Krüger, Olaf Hiort, Petra Seemann, Stefan Mundlos
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  ABSTRACT: Autosomal-dominant brachydactyly type E (BDE) is a congenital limb malformation characterized by small hands and feet predominantly as a result of shortened metacarpals and metatarsals. In a large pedigree with BDE, short stature, and learning disabilities, we detected a microdeletion of approximately 900 kb encompassing PTHLH, the gene coding for parathyroid hormone related protein (PTHRP). PTHRP is known to regulate the balance between chondrocyte proliferation and the onset of hypertrophic differentiation during endochondral bone development. Inactivation of Pthrp in mice results in short-limbed dwarfism because of premature differentiation of chondrocyte. On the basis of our initial finding, we tested further individuals with BDE and short stature for mutations in PTHLH. We identified two missense (L44P and L60P), a nonstop (X178WextX( *)54), and a nonsense (K120X) mutation. The missense mutation L60P was tested in chicken micromass culture with the replication-competent avian sarcoma leukosis virus retroviral expression system and was shown to result in a loss of function. Thus, loss-of-function mutations in PTHLH cause BDE with short stature.
  The American Journal of Human Genetics 02/2010; 86(3):434-9. · 10.60 Impact Factor
• Article: Array comparative genomic hybridization as a diagnostic tool for syndromic heart defects.

  Jeroen Breckpot, Bernard Thienpont, Hilde Peeters, Thomy de Ravel, Amihood Singer, Maissa Rayyan, Karel Allegaert, Christine Vanhole, Benedicte Eyskens, Joris Robert Vermeesch, Marc Gewillig, Koenraad Devriendt
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  ABSTRACT: To investigate different aspects of the introduction of array comparative genomic hybridization (aCGH) in clinical practice. A total 150 patients with a syndromic congenital heart defect (CHD) of unknown cause were analyzed with aCGH at 1-Mb resolution. Twenty-nine of these patients, with normal results on 1Mb aCGH, underwent re-analysis with 244-K oligo-microarray. With a logistic regression model, we assessed the predictive value of patient characteristics for causal imbalance detection. On the basis of our earlier experience and the literature, we constructed an algorithm to evaluate the causality of copy number variants. With 1-Mb aCGH, we detected 43 structural variants not listed as clinically neutral polymorphisms, 26 of which were considered to be causal. A systematic comparison of the clinical features of these 26 patients to the remaining 124 patients revealed dysmorphism as the only feature with a significant predictive value for reaching a diagnosis with 1-Mb aCGH. With higher resolution analysis in 29 patients, 75 variants not listed as clinically neutral polymorphisms were detected, 2 of which were considered to be causal. Molecular karyotyping yields an etiological diagnosis in at least 18% of patients with a syndromic CHD. Higher resolution evaluation results in an increasing number of variants of unknown significance.
  The Journal of pediatrics 02/2010; 156(5):810-7, 817.e1-817.e4. · 4.02 Impact Factor
• Article: Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations.

  Ellen Denayer, Koen Devriendt, Thomy de Ravel, Griet Van Buggenhout, Eric Smeets, Inge Francois, Yves Sznajer, Margarita Craen, George Leventopoulos, Léon Mutesa, Willy Vandecasseye, Guy Massa, Hulya Kayserili, Raf Sciot, Jean-Pierre Fryns, Eric Legius
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  ABSTRACT: Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in PTPN11, KRAS, SOS1, and RAF1. We performed SOS1, RAF1, BRAF, MEK1, and MEK2 mutation analysis in a cohort of 102 PTPN11- and KRAS-negative NS patients and found pathogenic SOS1 mutations in 10, RAF1 mutations in 4, and BRAF mutations in 2 patients. Three novel SOS1 mutations were found. One was classified as a rare benign variant and the other remains unclassified. We confirm a high prevalence of pulmonic stenosis and ectodermal abnormalities in SOS1-positive patients. Three patients with SOS1 mutations presented with tumors (embryonal rhabdomyosarcoma, Sertoli cell testis tumor, and granular cell tumors of the skin). One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations.
  Genes Chromosomes and Cancer 12/2009; 49(3):242-52. · 3.31 Impact Factor
• Article: A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion.

  Luis M Franco, Thomy de Ravel, Brett H Graham, Stephanie M Frenkel, Jozef Van Driessche, Pawel Stankiewicz, James R Lupski, Joris R Vermeesch, Sau Wai Cheung
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  ABSTRACT: Genomic rearrangements are an increasingly recognized mechanism of human phenotypic variation and susceptibility to disease. Sotos syndrome is characterized by overgrowth, macrocephaly, developmental delay and advanced osseous maturation. Haploinsufficiency of NSD1, caused by inactivating point mutations or deletion copy number variants, is the only known cause of Sotos syndrome. A recurrent 2 Mb deletion has been described with variable frequency in different populations. In this study, we report two individuals of different ethnic and geographical backgrounds, with duplications reciprocal to the common Sotos syndrome deletion. Our findings provide evidence for the existence of a novel syndrome of short stature, microcephaly, delayed bone development, speech delay and mild or absent facial dysmorphism. The phenotype is remarkably opposite to that of Sotos syndrome, suggesting a role for NSD1 in the regulation of somatic growth in humans.
  European journal of human genetics: EJHG 10/2009; 18(2):258-61. · 3.56 Impact Factor
• Article: Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant.

  Nadia Bahi-Buisson, Juliette Nectoux, Benoit Girard, Hilde Van Esch, Thomy De Ravel, Nathalie Boddaert, Perrine Plouin, Marlene Rio, Yann Fichou, Jamel Chelly, Thierry Bienvenu
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  ABSTRACT: The Forkhead box G1 (FOXG1) is a transcription factor that is critical for forebrain development, where it promotes progenitor proliferation and suppresses premature neurogenesis. Recently, the FOXG1 gene was implicated in the molecular aetiology of the congenital variant of Rett syndrome. So far, 15 FOXG1 molecular alterations, including only eight point mutations, have been reported. We screened the FOXG1 gene in a cohort of 206 MECP2 and CDKL5 mutation negative patients (136 females and 70 males) with severe encephalopathy and microcephaly. The screening was negative in all males, but two de novo mutations (c.1248C>G, p.Y416X and c.460_461dupG, p.E154GfsX300) were identified in two unrelated girls. Both patients showed neurological symptoms from the neonatal period with poor reactivity, hypotonia, and severe microcephaly. During the first year of life, both patients had feeding difficulties and made slow developmental progress. At 5 years old, the girls were significantly neurologically impaired with gross hypotonia, no language, convergent strabismus, and no voluntary hand use. Moreover, they presented a combination of jerky movements, hand-mouthing, and hand-washing stereotypies. Hence, FOXG1 mutation patients demonstrate severe encephalopathy compatible with the congenital variant, as well as additional features such as absent eye contact, inconsolable crying during the perinatal period, and delayed myelination with thin to hypoplastic corpus callosum. Although the overall frequency of mutations in FOXG1 in females with severe mental retardation and microcephaly appears to be low (1.5%), our findings suggest the requirement to investigate both point mutations and gene dosage in the FOXG1 gene in patients with severe encephalopathy with microcephaly and some Rett-like features.
  Neurogenetics 10/2009; 11(2):241-9. · 3.35 Impact Factor
• Article: Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia.

  Ingo Kurth, Eva Klopocki, Sigmar Stricker, Jolieke van Oosterwijk, Sebastian Vanek, Jens Altmann, Heliosa G Santos, Jeske J T van Harssel, Thomy de Ravel, Andrew O M Wilkie, Andreas Gal, Stefan Mundlos
  Nature Genetics 09/2009; 41(8):862-3. · 35.53 Impact Factor
• Source

  Available from: Joris Vermeesch

  Article: 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction.

  B Grisart, L Willatt, A Destrée, J-P Fryns, K Rack, T de Ravel, J Rosenfeld, J R Vermeesch, C Verellen-Dumoulin, R Sandford
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  ABSTRACT: Microdeletions at 17q21.31 have recently been shown to cause a novel syndrome. Here we identify the reciprocal 17q21.31 duplication syndrome in 4 patients. Patients with the 17q21.31 duplication were identified by screening a large cohort of patients (n = 13,070) with mental retardation and congenital malformation by comparative genomic hybridisation microarray. Parental origin was investigated in 3 patients by quantitative polymerase chain reaction and microsatellite genotyping. In three cases it was possible to show that duplication arose de novo. Intellectual skills range from normal to mild mental retardation. Patients are characterised by poor social interaction, with relationship difficulties, reminiscent of autistic spectrum disorders. Other features are rather variable with no striking common phenotypic features. Parental origin was investigated for 3 patients. In all cases duplication was of maternal origin either through interchromosomal (2 cases) or interchromatid (1 case) rearrangement. The 3 mothers are all carriers of the inverted H2 haplotype, emphasising the role of local genomic architecture alteration as a predisposing factor for this duplication. Autistic features observed in our patients suggest that genes in the duplicated interval should be considered as candidates for disorders in the autistic spectrum. Other phenotypic observations are rather variable or aspecific. This adds 17q21.31 duplications to a growing group of recently identified genomic disorders with variable penetrance and expressivity.
  Journal of Medical Genetics 07/2009; 46(8):524-30. · 6.36 Impact Factor
• Article: Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1.

  Hilde Brems, Eline Beert, Thomy de Ravel, Eric Legius
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  ABSTRACT: Neurofibromatosis type 1 (NF1) is a familial tumour syndrome. Malignant tumours can arise in the nervous and non-nervous system in either childhood or adulthood, with malignant peripheral nerve sheath tumours being most common. Rhabdomyosarcoma and neuroblastoma are paediatric neoplasms that are more common in children with NF1 than in those without the syndrome. Gastrointestinal stromal tumours, somatostatinomas, breast cancer, and phaeochromocytomas are seen in adults with NF1. Several pathways are thought to be involved in the development of tumours associated with NF1: rat sarcoma viral oncogene homologue (RAS)-mitogen activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), and P21 protein (Cdc42/Rac)-activated kinase 1 (PAK1). New insights into the pathogenesis of these tumours will lead to a better understanding of tumour origin and development and will hopefully allow the discovery of new and specific treatments.
  The lancet oncology 06/2009; 10(5):508-15. · 14.47 Impact Factor