Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mol Autism. 2021 Oct 6;12(1):65. doi: 10.1186/s13229-021-00465-3.
The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV).
SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes.
Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy.
The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification.
In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD.
自闭症谱系障碍（ASD）的全基因组关联研究鉴定了 102 个高度置信的 ASD 基因，表明 ASD 患者中携带这些基因的潜在有害单核苷酸变异（pdSNV），与不携带 pdSNV 的 ASD 参与者相比，其认知水平较低，行走年龄延迟。在这里，我们利用瑞典的 ASD 患者样本（称为 PAGES，即基于人群的自闭症遗传学和环境研究），使用流行病学框架和普遍健康报告，评估 pdSNV 的频率及其对医疗和精神疾病表型的影响。然后，我们将这些发现与潜在有害拷贝数变异（pdCNV）的发现相结合。
分别从全外显子测序和染色体微阵列数据中生成 SNV 和 CNV 调用。使用出生和医疗登记数据收集表型。
在接受测序评估的 808 名个体中，有 69 名（9%）在 102 个 ASC 基因中携带 pdSNV，144 名（18%）在 102 个 ASC 基因或更大的经修饰的神经发育基因中携带 pdSNV（来自解析发育障碍研究、基因表型数据库和拉德堡德大学基因列表）。有 3 名或更多个体在 GRIN2B、POGZ、SATB1、DYNC1H1、SCN8A 或 CREBBP 中携带 pdSNV。相比之下，在 996 名被调用 CNV 的个体中，有 105 名（11%）携带一个或多个 pdCNV，包括在复发性 15q11q13、22q11.2 和 16p11.2 位点携带 4 个或更多个体的 CNV。携带 pdSNV 的个体更有可能患有智力障碍（ID）和癫痫，而携带 pdCNV 的个体则显示出先天性异常和学业技能障碍的发生率增加。携带 pdSNV 或 pdCNV 的个体更有可能患有 ID、学业技能障碍和癫痫。
该队列仅包括患有自闭症障碍（ASD）的个体，即更严重的 ASD 形式，且表型是从医疗登记中定义的。并非所有研究的基因都是明确的 ASD 基因，我们没有新的信息来帮助分类。
在这个流行病学样本中，罕见的 pdSNV 比 pdCNV 更常见，潜在有害变异的总发生率为 27%。这些结果为将高通量测序作为 ASD 常规临床评估的一部分提供了有力的理由，并支持 ASD 精准医学的发展。
