Bowling Kevin M, Thompson Michelle L, Amaral Michelle D, Finnila Candice R, Hiatt Susan M, Engel Krysta L, Cochran J Nicholas, Brothers Kyle B, East Kelly M, Gray David E, Kelley Whitley V, Lamb Neil E, Lose Edward J, Rich Carla A, Simmons Shirley, Whittle Jana S, Weaver Benjamin T, Nesmith Amy S, Myers Richard M, Barsh Gregory S, Bebin E Martina, Cooper Gregory M
HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL, 35806, USA.
University of Louisville, Louisville, KY, USA.
Genome Med. 2017 May 30;9(1):43. doi: 10.1186/s13073-017-0433-1.
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.
发育障碍有多种遗传病因，必须加以识别以促进精确诊断。我们描述了371名受影响个体的基因组数据，其中309名作为先证者-父母三联体进行了测序。
对365名个体（127名受影响）进行了全外显子组测序（WES），对612名个体（244名受影响）进行了全基因组测序（WGS）。
在100名个体（27%）中发现了致病或可能致病的变异，另有42名个体（11.3%）存在意义不确定的变异。我们发现，神经疾病家族史，尤其是存在受影响的一级亲属，会降低致病/可能致病变异的识别率，这既反映了疾病的相关性，也反映了新发变异解释的难易程度。我们还发现，遗传知识的改进在许多情况下促进了解释的改变。通过系统的重新分析，我们迄今已重新分类了15个变异，最初被发现携带意义不确定变异的家族中有11.3%，最终结果为阴性的家族中有4.7%最终被发现携带致病或可能致病的变异。为了进一步推动这一进展，此处描述的数据正在通过ClinVar、GeneMatcher和dbGaP共享。
我们的数据有力地支持了大规模测序的价值，尤其是先证者-父母三联体内的全基因组测序，它既是一种有效的首选诊断工具，也是推进与小儿神经疾病相关的临床和研究进展的手段。
