Thalita Figueiredo1, Uirá Souto Melo2, André Luiz Santos Pessoa3, Paulo Ribeiro Nobrega4, João Paulo Kitajima5, Igor Correa5, Mayana Zatz2, Fernando Kok6, Silvana Santos1. 1. Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil Department of Biology, Paraiba State University (UEPB), Campina Grande, PB, Brazil. 2. Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. 3. Department of Neurology, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil Fortaleza University (UNIFOR), Fortaleza, CE, Brazil. 4. Department of Neurology, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. 5. Mendelics Genomic Analysis, Sao Paulo, SP, Brazil. 6. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: T Figueiredo; U S Melo; A L S Pessoa; P R Nobrega; J P Kitajima; H Rusch; F Vaz; L T Lucato; M Zatz; F Kok; S Santos Journal: Mol Psychiatry Date: 2015-09-29 Impact factor: 15.992