CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems

BACKGROUND: The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking. METHODS: We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder. RESULTS: Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene. CONCLUSIONS: The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals

Phosphorylation-independent desensitization of GABA(B) receptor by GRK4

Agonist-promoted desensitization of the heterodimeric metabotropic GABA(B) receptor was investigated. Whereas no desensitization was observed in HEK293 cells heterologously expressing the receptor, GABA and the synthetic agonist baclofen induced a robust desensitization in cerebellar granule cells endogenously expressing the receptor. Taking advantage of this cell-specific desensitization phenotype, we identified GRK4 as the kinase involved in the neuronal desensitization. Transfection of small interference RNA directed against GRK4 significantly reduced GRK4 levels in cerebellar granule cells and strongly inhibited the agonist-promoted desensitization. Reciprocally, transfection of GRK4 in HEK293 cells restored agonist-promoted desensitization, confirming that this kinase is sufficient to support desensitization. Surprisingly, this desensitization occurred in the absence of ligand-induced receptor phosphorylation and could be promoted by GRK4 mutants deleted of their kinase domain. Taken together, these results suggest that GRK4 plays a central role in the agonist-promoted desensitization of GABA(B) receptor and that it does so through an atypical mechanism that challenges the generally accepted model linking the kinase activity of GRKs to their role in receptor desensitization

Comparison of genome-wide array genomic hybridization platforms for the detection of copy number variants in idiopathic mental retardation

Background: Clinical laboratories are adopting array genomic hybridization as a standard clinical test. A number of whole genome array genomic hybridization platforms are available, but little is known about their comparative performance in a clinical context. Methods: We studied 30 children with idiopathic MR and both unaffected parents of each child using Affymetrix 500 K GeneChip SNP arrays, Agilent Human Genome 244 K oligonucleotide arrays and NimbleGen 385 K Whole-Genome oligonucleotide arrays. We also determined whether CNVs called on these platforms were detected by Illumina Hap550 beadchips or SMRT 32 K BAC whole genome tiling arrays and tested 15 of the 30 trios on Affymetrix 6.0 SNP arrays. Results: The Affymetrix 500 K, Agilent and NimbleGen platforms identified 3061 autosomal and 117 X chromosomal CNVs in the 30 trios. 147 of these CNVs appeared to be de novo, but only 34 (22%) were found on more than one platform. Performing genotype-phenotype correlations, we identified 7 most likely pathogenic and 2 possibly pathogenic CNVs for MR. All 9 of these putatively pathogenic CNVs were detected by the Affymetrix 500 K, Agilent, NimbleGen and the Illumina arrays, and 5 were found by the SMRT BAC array. Both putatively pathogenic CNVs identified in the 15 trios tested with the Affymetrix 6.0 were identified by this platform. Conclusions: Our findings demonstrate that different results are obtained with different platforms and illustrate the trade-off that exists between sensitivity and specificity. The large number of apparently false positive CNV calls on each of the platforms supports the need for validating clinically important findings with a different technology.Medical Genetics, Department ofMedicine, Faculty ofOther UBCNon UBCReviewedFacult

Appel nominal sur la question : "y a-t-il lieu à accusation contre le représentant du peuple Carrier ?", lors de la séance du 3 frimaire an III (23 novembre 1794)

Delaunay Pierre-Marie, Bernard de Saintes, Dugenne François-Elie, Pénières Jean Augustin, Bourdon (du Loiret), Guérin Pierre, Lombard-Lachaux Pierre, Le Clerc Claude-Nicolas, Dartigoeyte Pierre-Arnaud, Veau de Launay Pierre Louis Athanase, Bodin Pierre-Joseph-François, Duval Charles-François-Marie, Sevestre Joseph-Marie-François, Cambon Pierre-Joseph, Bousquet François, Ichon Pierre-Louis, Chazal Jean-Pierre, Chambon [La Tour] Jean Michel, Julien Jean, Lomont Claude-Jean-Baptiste, Bô Jean-Baptiste, Gaston Raymond, Clauzel Jean-Baptiste, Belley Jean-Baptiste, Jeannest Pierre-Edme-Nicolas, Bourbotte Pierre, Maure Nicolas-Sylvestre, Montégut Etienne-François-Sébastien, Pémartin Joseph, Romme Gilbert, Billaud-Varenne, Fréron Louis-marie-stanislas, Collot d'Herbois Jean-Marie, Boyaval Charles-Louis-Laurent, Lesage-Senault Gaspard-Jean-Joseph, Duhem Pierre-Joseph, Lefiot Jean-Alban, Thirion Didier, Couturier Jacob, Lequinio Marie-Joseph, Génin Jean françois, Roussel Claude-Jean De La Porte-Latine, Legendre (de Paris) Louis, Laurent Claude-hilaire, Bentabole Pierre-Louis, Pointe Noël, Patrin Eugène-melchior-louis, Le Cointre Laurent, Tallien Jean-Lambert, Chénier Marie-Joseph de, Dupuis Charles-françois, Albitte Antoine-Louis, Lofficial Louis-Prosper, Gaudin Joseph-Marie-Jacques-François, Maignen François, Ingrand François-Pierre, Milhaud Jean-Baptiste. Appel nominal sur la question : "y a-t-il lieu à accusation contre le représentant du peuple Carrier ?", lors de la séance du 3 frimaire an III (23 novembre 1794). In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome CII - Du 1er au 12 frimaire An III (21 novembre au 2 décembre 1794) Paris : CNRS éditions, 2012. pp. 99-117