title: KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature.
abstract: An increasing number of neurodevelopmental diseases have been associated with disruption of chromatin remodeling in eukaryotes. Lysine(K)-specific demethylase 5C (KDM5C) is a versatile epigenetic regulator that removes di- and tri-methyl groups of lysine 4 on histone H3 (H3K4) from transcriptional targets and is essential for neuronal survival and dendritic growth. Mutations in KDM5C gene, located at Xp11.22, have been reported as an important cause of both syndromic and non-syndromic X-linked intellectual disability (XLID) in males. The aim of this study was to evaluate the prevalence and spectrum of KDM5C mutations among Brazilian patients with XLID. To access the impact of KDM5C variants on XLID, a cohort of 143 males with a family history of intellectual disability (ID) suggestive of X-linked inheritance were enrolled. Common genetic causes of XLID were previously excluded and the entire coding and flanking intronic sequences of KDM5C gene were screened by direct Sanger sequencing. Seven nucleotide changes were observed: one pathogenic mutation (c.2172C>A, p.Cys724*), one novel variant with unknown value (c.633G>C, p.Arg211Arg) and five apparently benign sequence changes. In silico analysis of the variants revealed a putative creation of an Exonic Splicing Enhancer sequence by the silent c.633G>C mutation, which co-segregates with the ID phenotype. Our results point out to a KDM5C pathogenic mutational frequency of 0.7% among males with probable XLID. This is the first KDM5C screening among ID males from a country in Latin America and provides new clues about the significance of KDM5C mutations for genetic counseling.
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Thainá Fernandez
authors.initials: TF
authors.lastname: Gonçalves
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Andressa Pereira
authors.initials: AP
authors.lastname: Gonçalves
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fintelman Rodrigues
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Jussara Mendonça
authors.initials: JM
authors.lastname: dos Santos
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Márcia Mattos Gonçalves
authors.initials: MM
authors.lastname: Pimentel
authors.affiliation: Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: cbs@alternex.com.br.
authors.forename: Cíntia Barros
authors.initials: CB
authors.lastname: Santos-Rebouças
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001938:Brazil / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D050172:Genes, X-Linked / Q000235:genetics*; D005820:Genetic Testing; D056466:Histone Demethylases; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010375:Pedigree; D015995:Prevalence; D055815:Young Adult
chemical_list: D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating
keywords: Chromatin remodeling; Epigenetics; Histone demethylase; JARID1C; KDM5C; X-linked intellectual disability