Genomic diagnosis for children with intellectual disability and/or developmental delay.
Genomic diagnosis for children with intellectual disability and/or developmental delay.
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DOI：
10.1186/s13073-017-0433-1
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发表时间：
2017-05-30
期刊：
影响因子：
12.3
通讯作者：
Cooper GM
中科院分区：
文献类型：
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作者：
Bowling KM;Thompson ML;Amaral MD;Finnila CR;Hiatt SM;Engel KL;Cochran JN;Brothers KB;East KM;Gray DE;Kelley WV;Lamb NE;Lose EJ;Rich CA;Simmons S;Whittle JS;Weaver BT;Nesmith AS;Myers RM;Barsh GS;Bebin EM;Cooper GM
发育性残疾有多种遗传原因，必须加以确定，以促进准确的诊断。我们描述了来自371个受影响个体的基因组数据，其中309个被测序为先证者-父母三人组。为365个个体（127个受影响）生成全外显子组序列（WES），并为612个个体（244个受影响）生成全基因组序列（WGS）。在100名个体（27%）中发现了致病性或可能致病性变异，另外42名个体（11.3%）中发现了意义不确定的变异。我们发现，神经系统疾病的家族史，特别是受影响的一级亲属的存在，降低了致病性/可能致病性变异的识别率，反映了疾病的相关性和新发变异的易于解释。我们还发现，遗传知识的提高在许多情况下促进了解释的变化。通过系统的再分析，我们迄今已重新分类了15种变异，其中11.3%的最初被发现携带VUS的家庭和4.7%的阴性结果家庭最终被发现携带致病性或可能致病的变异。为了进一步推动这一进展，本文所述的数据正在通过ClinVar、GeneMatcher和dbGaP共享。我们的数据强烈支持大规模测序的价值，特别是先证者-父母三人组中的WGS，作为一种有效的首选诊断工具和促进儿科神经系统疾病相关临床和研究进展的手段。本文的在线版本（doi：10.1186/s13073-017-0433-1）包含补充材料，可供授权用户使用。
Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease. The online version of this article (doi:10.1186/s13073-017-0433-1) contains supplementary material, which is available to authorized users.