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Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family
  1. Thalita Figueiredo1,2,
  2. Uirá Souto Melo3,
  3. André Luiz Santos Pessoa4,5,
  4. Paulo Ribeiro Nobrega4,
  5. João Paulo Kitajima6,
  6. Igor Correa6,
  7. Mayana Zatz3,
  8. Fernando Kok3,4,
  9. Silvana Santos1,2
  1. 1Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil
  2. 2Department of Biology, Paraiba State University (UEPB), Campina Grande, PB, Brazil
  3. 3Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP, Brazil
  4. 4Department of Neurology, School of Medicine, University of Sao Paulo (USP), Sao Paulo, SP, Brazil
  5. 5Fortaleza University (UNIFOR), Fortaleza, CE, Brazil
  6. 6Mendelics Genomic Analysis, Sao Paulo, SP, Brazil
  1. Correspondence to Professor Silvana Santos, Department of Biology, Paraíba State University, Rua das Baraúnas, 351, Bodocongó, Campina Grande, Paraiba 58.410-367, Brazil; silvanasantos{at}ccbs.uepb.edu.br

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.

  • Molecular genetics
  • Clinical genetics

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