Xing Jinchuan, Lodi Mudassir, Flax Judy, Gwin Christine, Wilson Sherri, Robinson Amber, Buyske Steven, Brzustowicz Linda, Bartlett Chris
Rutgers, the State University of New Jersey.
Rutgers University.
Res Sq. 2025 May 6:rs.3.rs-5457750. doi: 10.21203/rs.3.rs-5457750/v1.
Autism spectrum disorder is a heritable neurodevelopmental condition that displays heterogeneity in both presentation and etiology and it often presents with concomitant communication difficulties. The hypothesis behind the New Jersey Language and Autism Genetic Study is that genetic heterogeneity for component phenotypes of autism spectrum disorder may be reduced relative to the disorder as a whole. We previously published an initial phase of this study with family recruitment that used very restricted inclusion/exclusion criteria for both autism and language deficits in other family members. Here we present an expanded sample that includes a wider range of phenotypic presentations in the autism and language domains. We found that our previous findings on 15q and 16q, connecting autism spectrum disorder and oral/written communication, are only relevant to the narrow autism spectrum disorder and language impairment phenotypes (with posterior probability of linkage of 57% and 33%, respectively) though addition of families did reduce both critical regions. After variant prioritization and additional filtration based on segregation patterns and functional annotations, we determined a set of 10 and 6 top candidate risk genes with strong association to language impairment and reading impairment, respectively. The top candidate genes include both genes previously implicated in neurodevelopmental disorders (e.g., and ) and genes not previously reported but with strong evidence of being involved in neurodevelopmental phenotypes.
自闭症谱系障碍是一种遗传性神经发育疾病，在临床表现和病因方面均表现出异质性，且常伴有沟通障碍。新泽西语言与自闭症遗传学研究背后的假设是，相对于自闭症谱系障碍整体而言，其组成表型的遗传异质性可能会降低。我们之前发表了该研究的初始阶段，其中的家庭招募对自闭症和其他家庭成员的语言缺陷使用了非常严格的纳入/排除标准。在此，我们展示了一个扩大后的样本，该样本在自闭症和语言领域包含了更广泛的表型表现。我们发现，我们之前关于15号染色体长臂和16号染色体长臂、将自闭症谱系障碍与口头/书面沟通联系起来的研究结果，仅与狭义的自闭症谱系障碍和语言障碍表型相关（连锁的后验概率分别为57%和33%），尽管增加家庭样本确实缩小了这两个关键区域。在根据分离模式和功能注释对变异进行优先级排序和额外筛选后，我们分别确定了一组与语言障碍和阅读障碍有强关联的10个和6个顶级候选风险基因。顶级候选基因既包括先前与神经发育障碍有关的基因（例如……），也包括先前未报道但有强有力证据表明参与神经发育表型的基因。
