Exploratory genetic analysis in children with autism spectrum disorder and other developmental disorders using whole exome sequencing

Edin Hamzic, Lemana Spahić, Nirvana Pistoljevic, Eldin Dzanko, Sanela Pasic, Lejla Kadric, F. Serdarevic, A. Hajdarpasic
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Abstract

Developmental disorders (DDs), such as autism spectrum disorder (ASD), incorporate various conditions; once identified, further diagnostics are necessary to specify their type and severity. The aim of this exploratory study was to identify genetic variants that can help differentiate ASD early from other DDs. We selected 36 children (mean age 60.1 months) with DDs using Developmental Behavioral Scales (DBS) through “EDUS-Education for All”, an organization providing services for children with developmental disorders in Bosnia and Herzegovina. We further rated children's autistic traits with the preschool version of the Childhood Autism Rating Scale, second edition (CARS-II). We defined ASD if scores were >25.5 and other DDs if scores were <25.5. Diagnosis of ASD and DD were independently confirmed by child psychiatrists. Whole exome sequencing was performed by Veritas Genetics, USA, using Illumina NovaSeq 6000 (Illumina Inc., San Diego, CA, USA) NGS sequencing apparatus. We tested genetic association by applying SKAT-O, which optimally combines the standard Sequence Kernel Association Test (SKAT) and burden tests to identify rare variants associated with complex traits in samples of limited power. The analysis yielded seven genes (DSE, COL10A1, DLK2, CSMD1, FAM47E, PPIA, PYDC2) to potentially differentiate observed phenotypic characteristics between our cohort participants with ASD and other DDs. Our exploratory study in a small sample of participants with ASD and other DDs contributed to gene discovery in differentiating ASD from DDs. A replication study is needed in a larger sample to confirm our results.
利用全外显子组测序对自闭症谱系障碍和其他发育障碍儿童进行探索性遗传分析
发育障碍(DDs),如自闭症谱系障碍(ASD),包含多种情况;一旦确定,就需要进一步诊断以明确其类型和严重程度。这项探索性研究的目的是找出有助于早期区分自闭症和其他发育障碍的基因变异。我们通过为波斯尼亚和黑塞哥维那发育障碍儿童提供服务的机构 "EDUS-全民教育",使用发育行为量表(DBS)选取了 36 名发育障碍儿童(平均年龄 60.1 个月)。我们还使用学龄前儿童自闭症评定量表第二版(CARS-II)对儿童的自闭症特征进行了评定。如果得分大于 25.5 分,我们将其定义为 ASD;如果得分小于 25.5 分,我们将其定义为其他 DD。ASD和DD的诊断均由儿童精神科医生独立确认。全外显子组测序由美国 Veritas Genetics 公司使用 Illumina NovaSeq 6000(Illumina Inc.我们采用 SKAT-O 测试遗传关联,该方法优化组合了标准序列核关联测试(SKAT)和负荷测试,以在有限的样本中找出与复杂性状相关的罕见变异。分析结果显示,七个基因(DSE、COL10A1、DLK2、CSMD1、FAM47E、PPIA、PYDC2)有可能区分我们队列中的 ASD 患者和其他 DD 患者的表型特征。我们在小样本 ASD 患者和其他 DD 患者中进行的探索性研究有助于发现区分 ASD 和 DD 的基因。我们需要在更大的样本中进行重复研究,以证实我们的结果。
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