Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA
J Med Genet. 2020 Sep;57(9):647-652. doi: 10.1136/jmedgenet-2019-106476. Epub 2020 Mar 9.
Autism typically presents with highly heterogeneous features, including frequent comorbidity with intellectual disability (ID). The overlap between these phenotypes has confounded the diagnosis and discovery of genetic factors associated with autism. We analysed pathogenic de novo genetic variants in individuals with autism who had either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity.
We analysed 2290 individuals from the Simons Simplex Collection for de novo likely gene-disruptive (LGD) variants and copy-number variants (CNVs), and determined their relevance towards IQ and Social Responsiveness Scale (SRS) measures.
Individuals who carried de novo variants in a set of 173 autism-associated genes showed an average 12.8-point decrease in IQ scores (p=5.49×10) and 2.8-point increase in SRS scores (p=0.013) compared with individuals without such variants. Furthermore, individuals with high-functioning autism (IQ >100) had lower frequencies of de novo LGD variants (42 of 397 vs 86 of 562, p=0.021) and CNVs (9 of 397 vs 24 of 562, p=0.065) compared with individuals who manifested both autism and ID (IQ <70). Pathogenic variants disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID, while de novo variants observed in individuals with high-functioning autism disrupted genes with little functional relevance towards neurodevelopment.
Pathogenic de novo variants disrupting autism-associated genes contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.
自闭症通常表现出高度异质的特征，包括与智力障碍（ID）频繁共病。这些表型的重叠使自闭症相关遗传因素的诊断和发现变得复杂。我们分析了自闭症患者中具有 ID 或正常认知功能的个体中的致病性新生遗传变异，以确定与自闭症相关的基因是否也与 ID 共病有关。
我们分析了来自 Simons Simplex Collection 的 2290 名个体的新生可能基因破坏性（LGD）变异和拷贝数变异（CNV），并确定了它们与智商和社会反应量表（SRS）测量值的相关性。
携带 173 个自闭症相关基因中新生变异的个体的智商得分平均下降 12.8 分（p=5.49×10），SRS 得分增加 2.8 分（p=0.013）与没有此类变异的个体相比。此外，高功能自闭症（智商>100）个体的新生 LGD 变异（42 例 397 例 vs. 86 例 562 例，p=0.021）和 CNV（9 例 397 例 vs. 24 例 562 例，p=0.065）的频率低于自闭症和 ID 均表现出的个体（智商<70）。破坏自闭症相关基因的致病性变异使共病 ID 的风险增加 4.85 倍（p=0.011），而在高功能自闭症个体中观察到的新生变异则破坏了对神经发育几乎没有功能相关性的基因。
破坏自闭症相关基因的新生致病性变异会导致自闭症和 ID 共病，而其他遗传因素可能是高功能自闭症的原因。
