title: Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family.
abstract: BACKGROUND
  Intellectual disability (ID) is a highly heterogeneous condition affecting 2% of the population worldwide. In a field study conducted in a highly inbred area of Northeastern Brazil, we investigated a consanguineous family in which seven adults presented syndromic ID.
  
  
  METHODS
  Genome-Wide Human SNP Array 6.0 (Affymetrix) microarray was used to determine regions of homozygosity-by-descent and whole exome sequencing (WES) was performed in one affected individual using Extended Nextera Rapid-Capture Exome and Illumina HiSeq2500.
  
  
  RESULTS
  We found two regions with an logarithm of the odds (LOD) score of 3.234: a region spanning 4.0 Mb in 19q13.32-q13.33 and a pericentromeric 20 Mb area in chromosome 2 (2p12-q11.2). WES disclosed in the critical region of chromosome 19 a homozygous variant (c.418C>T, p.Arg140Trp) in Mediator complex subunit 25 (MED25), predicted as deleterious by PolyPhen-2, Provean, Mutation Taster and Sorting Intolerant From Tolerant (SIFT). MED25 is a component of the Mediator complex, involved in regulation of transcription of nearly all RNA polymerase II-dependent genes. Deleterious mutations in MED12, MED17 and MED23 have already been associated with ID.
  
  
  CONCLUSIONS
  These findings demonstrate that the combination of field investigation of families in highly inbred regions with modern technologies is an effective way for identifying new genes associated with ID.
authors.affiliation: Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil Department of Biology, Paraiba State University (UEPB), Campina Grande, PB, Brazil.
authors.forename: Thalita
authors.initials: T
authors.lastname: Figueiredo
authors.affiliation: Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
authors.forename: Uirá Souto
authors.initials: US
authors.lastname: Melo
authors.affiliation: Department of Neurology, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil Fortaleza University (UNIFOR), Fortaleza, CE, Brazil.
authors.forename: André Luiz Santos
authors.initials: AL
authors.lastname: Pessoa
authors.affiliation: Department of Neurology, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
authors.forename: Paulo Ribeiro
authors.initials: PR
authors.lastname: Nobrega
authors.affiliation: Mendelics Genomic Analysis, Sao Paulo, SP, Brazil.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Kitajima
authors.affiliation: Mendelics Genomic Analysis, Sao Paulo, SP, Brazil.
authors.forename: Igor
authors.initials: I
authors.lastname: Correa
authors.affiliation: Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.affiliation: Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP, Brazil Department of Neurology, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil Department of Biology, Paraiba State University (UEPB), Campina Grande, PB, Brazil.
authors.forename: Silvana
authors.initials: S
authors.lastname: Santos
mesh_terms: D000328:Adult; D001483:Base Sequence; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D019066:Facies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: C483045:MED25 protein, human; D056892:Mediator Complex
keywords: Clinical genetics; Molecular genetics