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Márcia Mattos Gonçalves Pimentel - One of the best experts on this subject based on the ideXlab platform.
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a novel nonsense mutation in kdm5c jarid1c gene causing intellectual disability short stature and Speech Delay
Neuroscience Letters, 2011Co-Authors: Cintia Barros Santosreboucas, Lars R. Jensen, Andreas W. Kuss, Márcia Gonçalves Ribeiro, Mário Campos, Jussara Mendonça Dos Santos, Natalia Fintelmanrodrigues, Márcia Mattos Gonçalves PimentelAbstract:Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4 demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and differentiation. In this study, we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene with the intellectual disability phenotype. The transition resulted in replacement of the normal cysteine by a premature termination codon at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers and a mild cognitively impaired mother, consisted of short stature, Speech Delay, hyperactivity, violent behavior and high palate, besides severe mental retardation. Our findings extend the number of KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and unexplained cases of XLID.
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A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and Speech Delay
Neuroscience letters, 2011Co-Authors: Cíntia Barros Santos-rebouças, Natalia Fintelman-rodrigues, Lars R. Jensen, Andreas W. Kuss, Márcia Gonçalves Ribeiro, Mário Campos, Jussara Mendonça Dos Santos, Márcia Mattos Gonçalves PimentelAbstract:Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22, are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4 demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and differentiation. In this study, we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene with the intellectual disability phenotype. The transition resulted in replacement of the normal cysteine by a premature termination codon at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers and a mild cognitively impaired mother, consisted of short stature, Speech Delay, hyperactivity, violent behavior and high palate, besides severe mental retardation. Our findings extend the number of KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and unexplained cases of XLID.
Pawel Stankiewicz - One of the best experts on this subject based on the ideXlab platform.
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haploinsufficiency of the chromatin remodeler bptf causes syndromic developmental and Speech Delay postnatal microcephaly and dysmorphic features
American Journal of Human Genetics, 2017Co-Authors: Pawel Stankiewicz, Tahir Naeem Khan, Przemyslaw Szafranski, Leah Slattery, Haley Streff, Francesco Vetrini, Jonathan A Bernstein, Chester W BrownAbstract:Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental Delay/intellectual disability (10/10), Speech Delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.
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A syndrome of short stature, microcephaly and Speech Delay is associated with duplications reciprocal to the common Sotos syndrome deletion.
European journal of human genetics : EJHG, 2009Co-Authors: Luis M. Franco, Thomy De Ravel, Brett H. Graham, Stephanie M Frenkel, Jozef Van Driessche, Pawel Stankiewicz, James R. Lupski, Joris Vermeesch, Sau Wai CheungAbstract: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.
Almuth Caliebe - One of the best experts on this subject based on the ideXlab platform.
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four patients with Speech Delay seizures and variable corpus callosum thickness sharing a 0 440 mb deletion in region 1q44 containing the hnrpu gene
European Journal of Medical Genetics, 2010Co-Authors: Almuth Caliebe, Hester Y Kroes, Jose I Martinsubero, Holger Tonnies, Rutger A J Nievelstein, Hiltrud Muhle, Ulrich Stephani, Jasper J Van Der Smagt, Ruben Van T Slot, K AlfkeAbstract:Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental Delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental Delay, in particular of expressive Speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental Delay, Speech Delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration.
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four patients with Speech Delay seizures and variable corpus callosum thickness sharing a 0 440 mb deletion in region 1q44 containing the hnrpu gene
European Journal of Medical Genetics, 2010Co-Authors: Almuth Caliebe, Ruben Van T Slot, Hester Y Kroes, Jasper J Van Der Smagt, Jose I Martinsubero, Holger Tonnies, Rutger A J Nievelstein, Hiltrud Muhle, Ulrich Stephani, K AlfkeAbstract:Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental Delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental Delay, in particular of expressive Speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental Delay, Speech Delay, hypotonia, hypo-or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration. (C) 2010 Elsevier Masson SAS. All rights reserved.
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Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe Speech Delay.
American journal of medical genetics. Part A, 2006Co-Authors: Jörg Weimer, Simone Metzke-heidemann, Hansjörg Plendl, Almuth Caliebe, Regina Grunewald, Katrin Õunap, Pille Tammur, Walter Jonat, Oliver Bartsch, Reiner SiebertAbstract:A boy with signs of Klinefelter syndrome, mild facial dysmorphic features, and severely retarded Speech development displayed a female karyotype with mosaicism for two marker chromosomes 48,XX,+mar1,+mar2[68]/47,XX,+mar1[19]/47,XX,+mar2[6]/46,XX[8]. Using chromosomal microdissection, locus-specific fluorescence in situ hybridization (FISH), and PCR with several Y-chromosome markers, the larger supernumerary marker chromosome (SMC) was characterized as a ring Y-chromosome. Detection of the SRY-region explained the male phenotype. The smaller second marker chromosome contained the pericentromeric region of chromosome 8. We suggest that the co-occurrence of a partial Y-chromosome and partial trisomy 8 explain the severe Speech Delay and the facial dysmorphic features.
Barbara R. Dupont - One of the best experts on this subject based on the ideXlab platform.
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22q13.2q13.32 genomic regions associated with severity of Speech Delay, developmental Delay, and physical features in Phelan–McDermid syndrome
Genetics in Medicine, 2013Co-Authors: Sara M. Sarasua, Katy Phelan, R. Curtis Rogers, Luigi Boccuto, Jonathan D. Rollins, Julianne S. Collins, Alka Dwivedi, Chin-fu Chen, Julia L. Sharp, Barbara R. DupontAbstract:22q13.2q13.32 genomic regions associated with severity of Speech Delay, developmental Delay, and physical features in Phelan–McDermid syndrome
Reiner Siebert - One of the best experts on this subject based on the ideXlab platform.
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Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe Speech Delay.
American journal of medical genetics. Part A, 2006Co-Authors: Jörg Weimer, Simone Metzke-heidemann, Hansjörg Plendl, Almuth Caliebe, Regina Grunewald, Katrin Õunap, Pille Tammur, Walter Jonat, Oliver Bartsch, Reiner SiebertAbstract:A boy with signs of Klinefelter syndrome, mild facial dysmorphic features, and severely retarded Speech development displayed a female karyotype with mosaicism for two marker chromosomes 48,XX,+mar1,+mar2[68]/47,XX,+mar1[19]/47,XX,+mar2[6]/46,XX[8]. Using chromosomal microdissection, locus-specific fluorescence in situ hybridization (FISH), and PCR with several Y-chromosome markers, the larger supernumerary marker chromosome (SMC) was characterized as a ring Y-chromosome. Detection of the SRY-region explained the male phenotype. The smaller second marker chromosome contained the pericentromeric region of chromosome 8. We suggest that the co-occurrence of a partial Y-chromosome and partial trisomy 8 explain the severe Speech Delay and the facial dysmorphic features.