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Abstract：
The genotype-first approach has been successfully applied and has elucidated several subtypes of autism spectrum disorder (ASD). However, it requires very large cohorts because of the extensive genetic heterogeneity. We investigate the alternate possibility of whether phenotype-specific genes can be identified from a small group of patients with specific phenotype(s). To identify novel genes associated with ASD and abnormal head circumference using a phenotype-to-genotype approach, we performed whole-exome sequencing on 67 families with ASD and abnormal head circumference. Clinically relevant pathogenic or likely pathogenic variants account for 23.9% of patients with microcephaly or macrocephaly, and 81.25% of those variants or genes are head-size associated. Significantly, recurrent pathogenic mutations were identified in two macrocephaly genes (PTEN, CHD8) in this small cohort. De novo mutations in several candidate genes (UBN2, BIRC6, SYNE1, and KCNMA1) were detected, as well as one new candidate gene (TNPO3) implicated in ASD and related neurodevelopmental disorders. We identify genotype-phenotype correlations for head-size-associated ASD genes and novel candidate genes for further investigation. Our results also suggest a phenotype-to-genotype strategy would accelerate the elucidation of genotype-phenotype relationships for ASD by using phenotype-restricted cohorts.
摘要：
基因型优先方法已成功应用，并阐明了自闭症谱系障碍（ASD）的几种亚型。然而,由于广泛的遗传异质性，它需要非常大的队列。我们研究了是否可以从一小组具有特定表型的患者中鉴定出表型特异性基因的替代可能性。为了使用表型到基因型的方法鉴定与ASD和异常头围相关的新基因，我们对67个患有ASD和头围异常的家庭进行了全外显子组测序.临床相关的致病或可能的致病变异占23.9%的小头畸形或大头畸形患者，81.25%的变异或基因与头部大小相关。重要的是,在两个大头畸形基因(PTEN，CHD8）在这个小队列中。检测到几种候选基因（UBN2，BIRC6，SYNE1和KCNMA1）的从头突变，以及一个新的候选基因（TNPO3）与ASD和相关的神经发育障碍有关。我们确定了与头部大小相关的ASD基因和新的候选基因的基因型-表型相关性，以进行进一步研究。我们的结果还表明，通过使用表型限制的队列，表型到基因型的策略将加速阐明ASD的基因型-表型关系。
