在患有自闭症谱系障碍的不同临床儿童群体中进行包括靶向基因panel在内的基因检测：研究结果与启示。
Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.
作者信息
Kalsner Louisa, Twachtman-Bassett Jennifer, Tokarski Kristin, Stanley Christine, Dumont-Mathieu Thyde, Cotney Justin, Chamberlain Stormy
机构信息
Connecticut Children's Medical Center, Farmington, CT, USA.
University of Connecticut School of Medicine, Farmington, CT, USA.
出版信息
Mol Genet Genomic Med. 2018 Mar;6(2):171-185. doi: 10.1002/mgg3.354. Epub 2017 Dec 21.
BACKGROUND
Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well.
METHODS
We performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database.
RESULTS
We did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database.
CONCLUSION
The yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large-scale genomic databases used to identify variants that contribute to disease risk.
背景
对患有自闭症谱系障碍（ASD）的儿童进行基因检测如今在临床环境中已成为标准做法，美国医学遗传学与基因组学学会（ACMGG）的指南建议对所有儿童进行微阵列检测，对男孩进行脆性X检测，并对合适的患者进行包括PTEN和MECP2在内的额外基因测序。越来越多的检测也采用了高通量测序，包括基因panel和全外显子组测序。
方法
我们对100名特征明确的患有ASD的儿童进行了基因检测，包括微阵列检测、脆性X检测和靶向基因panel，持续对161个与ASD风险相关的基因进行测序。将在各个基因中鉴定出的罕见变异频率与外显子聚合联盟（ExAC）数据库中报告的频率进行比较。
结果
我们未诊断出任何对ASD具有完全外显率的病症；然而，在12%的病例中鉴定出了被认为会增加ASD风险的拷贝数变异。在基因panel上发现11名儿童可能存在致病变异，但经过仔细分析，没有一个被认为可能是疾病的病因。在6.7%的儿童中鉴定出了KIRREL3变异，而在ExAC中这一比例为2%，这表明KIRREL3变异在ASD风险中可能发挥作用。携带KIRREL3变异的儿童更常出现轻微面部畸形和智力残疾。我们还观察到TSC2中罕见变异有所增加。然而，对西蒙斯单基因队列研究的变异数据进行分析表明，TSC2中的罕见变异在特定种族/族裔群体中更常见，而这些群体在我们的研究人群中比在ExAC数据库中更为普遍。
结论
包括微阵列检测、脆性X检测（男孩）和靶向基因panel在内的基因检测阳性率为12%。基因panel并未提高诊断阳性率；然而，我们发现KIRREL3中的罕见变异有所增加。我们的研究结果强化了在用于识别导致疾病风险变异的大规模基因组数据库中纳入种族/族裔多样性的必要性。
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