Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brazil.
The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Clin Genet. 2022 Jan;101(1):134-141. doi: 10.1111/cge.14072. Epub 2021 Nov 15.
Prediction of pathogenicity of rare copy number variations (CNVs), a genomic alteration known to contribute to the etiology of autism spectrum disorder (ASD), represents a serious limitation to interpreting genetic tests, particularly for genetic counseling purposes. Chromosomal microarray analysis (CMA) was conducted in a unique collection of 144 Brazilian individuals with ASD of strong European and African ancestries. Rare CNVs were detected in 39 patients: 41 of unknown significance (VUS), four pathogenic and one likely pathogenic CNVs (clinical yield of 4.1%; 5/122). Based on gene content and recurrence in three large cohorts [a Brazilian neurodevelopmental disorder cohort, the autism MSSNG cohort, and the Canadian-based Centre for Applied Genomics microarray database], this work strengthened the pathogenicity of 14 genes (FAT1, CAMK4, BIRC6, DPP6, CSMD1, CTNNA3, CDH8/CDH11, CDH13, OR1C1, CNTN6, CNTNAP4, FGF2 and PTPRN2) within 14 CNVs. Notably, enrichment of cell adhesion proteins to ASD etiology was identified (p < 0.05), highlighting the importance of these gene families in the etiology of ASD.
预测罕见的拷贝数变异（CNVs）的致病性，这种基因组改变已知会导致自闭症谱系障碍（ASD）的病因，这代表了解释遗传测试的一个严重限制，特别是对于遗传咨询目的。在具有强烈欧洲和非洲血统的 144 名巴西 ASD 个体的独特集合中进行了染色体微阵列分析（CMA）。在 39 名患者中检测到罕见的 CNVs：41 个为意义不明（VUS），4 个为致病性和 1 个可能致病性 CNVs（临床检出率为 4.1%；5/122）。基于基因内容和三个大型队列中的复发情况[一个巴西神经发育障碍队列、自闭症 MSSNG 队列和加拿大应用基因组学微阵列数据库]，这项工作加强了 14 个基因（FAT1、CAMK4、BIRC6、DPP6、CSMD1、CTNNA3、CDH8/CDH11、CDH13、OR1C1、CNTN6、CNTNAP4、FGF2 和 PTPRN2）在 14 个 CNVs 中的致病性。值得注意的是，鉴定到了与 ASD 病因相关的细胞粘附蛋白的富集（p < 0.05），突出了这些基因家族在 ASD 病因学中的重要性。
