X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.
复制标题
DOI：
10.1038/mp.2014.193
复制
发表时间：
2016-01
影响因子：
11
通讯作者：
Kalscheuer VM
中科院分区：
文献类型：
--
作者：
Hu H;Haas SA;Chelly J;Van Esch H;Raynaud M;de Brouwer AP;Weinert S;Froyen G;Frints SG;Laumonnier F;Zemojtel T;Love MI;Richard H;Emde AK;Bienek M;Jensen C;Hambrock M;Fischer U;Langnick C;Feldkamp M;Wissink-Lindhout W;Lebrun N;Castelnau L;Rucci J;Montjean R;Dorseuil O;Billuart P;Stuhlmann T;Shaw M;Corbett MA;Gardner A;Willis-Owen S;Tan C;Friend KL;Belet S;van Roozendaal KE;Jimenez-Pocquet M;Moizard MP;Ronce N;Sun R;O'Keeffe S;Chenna R;van Bömmel A;Göke J;Hackett A;Field M;Christie L;Boyle J;Haan E;Nelson J;Turner G;Baynam G;Gillessen-Kaesbach G;Müller U;Steinberger D;Budny B;Badura-Stronka M;Latos-Bieleńska A;Ousager LB;Wieacker P;Rodríguez Criado G;Bondeson ML;Annerén G;Dufke A;Cohen M;Van Maldergem L;Vincent-Delorme C;Echenne B;Simon-Bouy B;Kleefstra T;Willemsen M;Fryns JP;Devriendt K;Ullmann R;Vingron M;Wrogemann K;Wienker TF;Tzschach A;van Bokhoven H;Gecz J;Jentsch TJ;Chen W;Ropers HH;Kalscheuer VM
X连锁智力障碍(XLID)是一种临床和遗传异质性疾病。在过去的二十年里，已经识别了100多个X染色体ID基因。然而，大量定位到X染色体的家系仍然没有得到解决，这表明还没有确定更多的XLID基因或基因座。在这里，我们调查了405个XLID未解决的家庭。我们对索引男性中的所有X染色体外显子进行了大规模平行测序。这些男性中的大多数之前通过Sanger测序检测出拷贝数变异和已知XLID基因子集的突变为阴性。共筛选出745个X染色体基因。经过严格筛选，共有1297个非重复外显子变异体保留下来进行优先排序。潜在临床相关变化的共分离分析显示，80个家系(20%)携带已建立的XLID基因的致病变异。在19个家系中，我们检测了7个新的和有效的XLID基因(CLCN4、CNKSR2、FRMPD4、KLHL15、LAS1L、RLIM和USP27X)可能的致病蛋白截断和错义变异，以及2个新的候选XLID基因(CDK16和TAF1)的潜在有害变异。电生理学研究表明，CLCN4和CNKSR2变异体削弱了蛋白质的功能，并改变了ClCN4−/−小鼠培养的原代神经元的分化或基因敲除后的分化。新发现的和候选的XLID蛋白属于通路和网络，在认知功能和智能障碍方面具有既定的作用。我们认为，对一组有X染色体基因涉及的遗传证据的患者进行所有X染色体基因的系统测序，可以解决高达58%的脆性X阴性病例。
X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.