Genome sequencing identifies major causes of severe intellectual disability
Genome sequencing identifies major causes of severe intellectual disability
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DOI：
10.1038/nature13394
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发表时间：
2014-07-17
期刊：
影响因子：
64.8
通讯作者：
Veltman, Joris A.
中科院分区：
文献类型：
--
作者：
Gilissen, Christian;Hehir-Kwa, Jayne Y.;Veltman, Joris A.
严重智力残疾（ID）发生在0.5%的新生儿中，被认为在很大程度上是遗传的（1,2）。这种疾病的广泛遗传异质性需要对所有类型的遗传变异进行全基因组检测。微阵列研究和最近的外显子组测序已经证明了新生拷贝数变异（CNVs）和单核苷酸变异（SNVs）在ID中的重要性，但大多数病例仍未被诊断（3-6）。在这里，我们对50名患有严重ID的患者及其未受影响的父母进行了全基因组测序。所有纳入的患者在广泛的遗传预筛选后均未接受分子诊断，包括基于微阵列的CNV研究和外显子组测序。尽管进行了这种预筛选，但仍鉴定出84个影响编码区的新生snv，这显示出具有统计学意义的功能丧失突变的富集，以及先前与id相关疾病相关的基因的富集。此外，我们鉴定了8个新的CNVs，包括单外显子和外显子内缺失，以及染色体间重复。这些CNVs比预期更频繁地影响已知的ID基因。在所有新生变异的诊断解释的基础上，20例患者获得了结论性的遗传诊断。再加上一种以隐性模式引起疾病的复合杂合CNV，在这个广泛研究的队列中，诊断率为42%，在一个未选择的队列中，累积估计值为62%。这些结果表明，影响编码区的新生SNVs和CNVs是严重ID的主要原因。基因组测序可以作为一种单一的基因检测，可靠地识别和表征遗传变异的综合谱，为大多数严重ID患者提供遗传诊断。
Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin(1,2). The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed(3-6). Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.