title: Novel microduplications at Xp11.22 including HUWE1: clinical and molecular insights into these genomic rearrangements associated with intellectual disability.
abstract: Recently, we defined a minimal overlapping region for causal Xp11.22 copy number gains in males with intellectual disability (ID), and identified HECT, UBA and WWE domain-containing protein-1 (HUWE1) as the primary dosage-sensitive gene, whose overexpression leads to ID. In the present study, we used this minimal interval to search for HUWE1 copy number variations by quantitative polymerase chain reaction in a large cohort of Brazilian males with idiopathic ID. We detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. Breakpoint junction analysis showed a simple tandem duplication in the first patient, which has probably arisen by microhomology-mediated break-induced repair mechanism. In the second patient, the rearrangement is complex having an insertion of an intrachromosomal sequence at its junction. This kind of rearrangement has not been reported in Xp11.22 duplications and might have emerged by a replication- or recombination-based mechanism. Furthermore, the presence of infantile seizures in the second family suggests a potential role of increased KDM5C expression on epilepsy. Our findings highlight the importance of microduplications at Xp11.22 to ID, even in sporadic cases, and reveal new clinical and molecular insight into HUWE1 copy number gains.
authors: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Cíntia Barros
authors: CB
authors: Santos-Rebouças
authors: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Luciana Guedes
authors: LG
authors: de Almeida
authors: 1] Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium [2] Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors: Stefanie
authors: S
authors: Belet
authors: Gaffrée and Guinle University Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro, Brazil.
authors: Suely Rodrigues
authors: SR
authors: Dos Santos
authors: Clinical Genetics Service, IPPMG, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Márcia Gonçalves
authors: MG
authors: Ribeiro
authors: Laboratory of Biotechnology, Center for Biosciences and Biotechnology, State University of North Fluminense Darcy Ribeiro, Rio de Janeiro, Brazil.
authors: Antônio Francisco Alves
authors: AF
authors: da Silva
authors: Laboratory of Biotechnology, Center for Biosciences and Biotechnology, State University of North Fluminense Darcy Ribeiro, Rio de Janeiro, Brazil.
authors: Enrique
authors: E
authors: Medina-Acosta
authors: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Jussara Mendonça
authors: JM
authors: Dos Santos
authors: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Andressa Pereira
authors: AP
authors: Gonçalves
authors: Department of Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Paulo Roberto Valle
authors: PR
authors: Bahia
authors: Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Márcia Mattos Gonçalves
authors: MM
authors: Pimentel
authors: 1] Human Genome Laboratory, VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium [2] Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors: Guy
authors: G
authors: Froyen
mesh_terms: D000293:Adolescent; D002648:Child; D058674:Chromosome Duplication; D041321:Chromosomes, Human, X; D056915:DNA Copy Number Variations; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010375:Pedigree; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases
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