Figueiredo Thalita, Melo Uirá Souto, Pessoa André Luiz Santos, Nobrega Paulo Ribeiro, Kitajima João Paulo, Correa Igor, Zatz Mayana, Kok Fernando, Santos Silvana
Northeast Biotechnology Network (RENORBIO), Federal University of Paraiba (UFPB), Joao Pessoa, PB, Brazil Department of Biology, Paraiba State University (UEPB), Campina Grande, PB, Brazil.
Human Genome and Stem Cell Research Center, Biosciences Institute, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.
J Med Genet. 2015 Feb;52(2):123-7. doi: 10.1136/jmedgenet-2014-102793. Epub 2014 Dec 19.
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.
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.
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.
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.
智力残疾（ID）是一种高度异质性疾病，影响着全球2%的人口。在巴西东北部一个高度近亲结婚的地区进行的一项实地研究中，我们调查了一个近亲家庭，其中七名成年人患有综合征性智力残疾。
使用全基因组人类SNP Array 6.0（Affymetrix）微阵列来确定同源纯合区域，并对一名受影响个体使用扩展Nextera快速捕获外显子组和Illumina HiSeq2500进行全外显子组测序（WES）。
我们发现了两个对数优势（LOD）得分为3.234的区域：一个位于19q13.32 - q13.33，跨度为4.0 Mb的区域，以及染色体2（2p12 - q11.2）上一个着丝粒周围20 Mb的区域。全外显子组测序在19号染色体的关键区域发现中介体复合物亚基25（MED25）中的一个纯合变异（c.418C>T，p.Arg140Trp），PolyPhen - 2、Provean、Mutation Taster和从耐受中筛选不耐受（SIFT）预测该变异有害。MED25是中介体复合物的一个组成部分，参与几乎所有RNA聚合酶II依赖性基因的转录调控。MED12、MED17和MED23中的有害突变已与智力残疾相关。
这些发现表明，在高度近亲结婚地区对家庭进行实地调查与现代技术相结合是鉴定与智力残疾相关新基因的有效方法。
