Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.
Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.
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DOI：
10.1007/s00439-018-1928-6
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发表时间：
2018-09
期刊：
影响因子：
5.3
通讯作者：
Leal SM
中科院分区：
文献类型：
--
作者：
Santos-Cortez RLP;Khan V;Khan FS;Mughal ZU;Chakchouk I;Lee K;Rasheed M;Hamza R;Acharya A;Ullah E;Saqib MAN;Abbe I;Ali G;Hassan MJ;Khan S;Azeem Z;Ullah I;Bamshad MJ;Nickerson DA;Schrauwen I;Ahmad W;Ansar M;Leal SM
使用外显子组测序来研究常染色体隐性遗传 (AR) 近亲血统，鉴定神经发育障碍的孟德尔基因已取得巨大成功。为了确定综合征性和非综合征性智力障碍 (ID) 的致病变异，使用来自 22 个患有 ARID 的巴基斯坦近亲家庭的 DNA 样本进行了外显子组测序，其中 21 个具有包括小头畸形在内的其他表型。为了帮助变异鉴定，进行了纯合性作图和连锁分析。来自每个谱系的受影响家庭成员的 DNA 样本都经过了外显子组测序。使用桑格测序测试了鉴定出的罕见破坏性外显子组变异与 ID 的共分离。对于七个 ARID 家族，在以前与 ID 无关的基因中发现了变异，包括：EI24、FXR1 和 TET3，这些基因敲除小鼠模型存在脑缺陷；以及 CACNG7 和 TRAPPC10，细胞研究表明它们在重要的神经通路中发挥作用。对于两个家族，新的 ARID 基因 CARNMT1 和 GARNL3 位于先前报道的 ID 微缺失区域内。我们还在两个 ID 候选基因 GRAMD1B 和 TBRG1 中观察到纯合变异，这两个基因先前已在单个家族中报道过。另外 14 个家族在已确定的 ID 基因中具有纯合变异，其中 11 个变异是新的。所有 ARID 基因在发育中和成人大脑的特定结构中表达增加，并且 91% 的基因在子宫内或幼儿期有差异表达。新型 ARID 候选基因和变异的鉴定增加了进一步了解人类大脑功能和发育所需的知识库。
Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.
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影响因子：
8.2
作者：
Fama, Rosemary;Sullivan, Edith V.
通讯作者：
Sullivan, Edith V.
影响因子：
1.3
作者：
Ehret JK;Engels H;Cremer K;Becker J;Zimmermann JP;Wohlleber E;Grasshoff U;Rossier E;Bonin M;Mangold E;Bevot A;Schön S;Heilmann-Heimbach S;Dennert N;Mathieu-Dramard M;Lacaze E;Plessis G;de Broca A;Jedraszak G;Röthlisberger B;Miny P;Filges I;Dufke A;Andrieux J;Lee JA;Zink AM
通讯作者：
Zink AM
影响因子：
11
作者：
Harripaul, R.;Vasli, N.;Vincent, J. B.
通讯作者：
Vincent, J. B.
影响因子：
4.8
作者：
Drozak, Jakub;Piecuch, Maria;de Heer, Emile
通讯作者：
de Heer, Emile
影响因子：
9.8
作者：
Garshasbi, Masoud;Hadavi, Valeh;Kuss, Andreas Walter
通讯作者：
Kuss, Andreas Walter