Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing
Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing
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DOI：
10.1136/jmedgenet-2013-101644
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发表时间：
2013-12-01
影响因子：
4
通讯作者：
de Brouwer, Arjan P. M.
中科院分区：
文献类型：
--
作者：
Schuurs-Hoeijmakers, Janneke H. M.;Vulto-van Silfhout, Anneke T.;de Brouwer, Arjan P. M.
背景智力残疾（ID）是一种常见的神经发育障碍，影响1-3%的普通人群。超过10%的所有人类基因的突变被认为是参与这种疾病，虽然这些基因中的大多数仍然是unknow.Objectives我们调查了19个小的非血缘家庭，两个到五个受影响的兄弟姐妹，以确定致病基因变异已知的，新的和潜在的ID候选基因。非血缘家庭在很大程度上被忽视的基因鉴定研究，小家庭规模排除了事先映射的遗传defect.Methods和结果使用外显子组测序，我们确定了致病性突变的三个基因，DDHD 2，SLC 6A 8，和SLC 9A 6，其中后两个以前被牵连在X-连锁ID表型。此外，我们确定了潜在的致病性突变BCORL 1的X染色体和MCM 3AP，PTPRT，SYNE 1，和ZNF 528的常染色体上。结论我们表明，潜在的致病性基因变异可以确定在小，非血缘关系的家庭，只有两个受影响的兄弟姐妹，从而强调他们的价值，在综合征和非综合征ID基因的识别。
Background Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown.Objectives We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect.Methods and results Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes.Conclusions We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.