Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family

J Med Genet. 2015 Feb;52(2):123-7. doi: 10.1136/jmedgenet-2014-102793. Epub 2014 Dec 19.


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.

Keywords: Clinical genetics; Molecular genetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Consanguinity*
  • Exome / genetics
  • Facies
  • Family
  • Female
  • Genetic Predisposition to Disease*
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Mediator Complex / genetics*
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Pedigree
  • Sequence Analysis, DNA


  • MED25 protein, human
  • Mediator Complex