FRIGE's Institute of Human Genetics, Ahmedabad, India.
Shishu Child Development and Early Intervention Centre, Ahmedabad, India.
BMC Neurol. 2023 Aug 5;23(1):292. doi: 10.1186/s12883-023-03341-0.
Autism spectrum disorder (ASD) affects 1 in 100 children globally with a rapidly increasing prevalence. To the best of our knowledge, no data exists on the genetic architecture of ASD in India. This study aimed to identify the genetic architecture of ASD in India and to assess the use of whole exome sequencing (WES) as a first-tier test instead of chromosomal microarray (CMA) for genetic diagnosis.
Between 2020 and 2022, 101 patient-parent trios of Indian origin diagnosed with ASD according to the Diagnostic and Statistical Manual, 5th edition, were recruited. All probands underwent a sequential genetic testing pathway consisting of karyotyping, Fragile-X testing (in male probands only), CMA and WES. Candidate variant validation and parental segregation analysis was performed using orthogonal methods.
Of 101 trios, no probands were identified with a gross chromosomal anomaly or Fragile-X. Three (2.9%) and 30 (29.7%) trios received a confirmed genetic diagnosis from CMA and WES, respectively. Amongst diagnosis from WES, SNVs were detected in 27 cases (90%) and CNVs in 3 cases (10%), including the 3 CNVs detected from CMA. Segregation analysis showed 66.6% (n = 3 for CNVs and n = 17 for SNVs) and 16.6% (n = 5) of the cases had de novo and recessive variants respectively, which is in concordance with the distribution of variant types and mode of inheritance observed in ASD patients of non-Hispanic white/ European ethnicity. MECP2 gene was the most recurrently mutated gene (n = 6; 20%) in the present cohort. Majority of the affected genes identified in the study cohort are involved in synaptic formation, transcription and its regulation, ubiquitination and chromatin remodeling.
Our study suggests de novo variants as a major cause of ASD in the Indian population, with Rett syndrome as the most commonly detected disorder. Furthermore, we provide evidence of a significant difference in the diagnostic yield between CMA (3%) and WES (30%) which supports the implementation of WES as a first-tier test for genetic diagnosis of ASD in India.
自闭症谱系障碍（ASD）影响全球每 100 名儿童中有 1 名，其患病率呈快速上升趋势。据我们所知，印度尚未有关于 ASD 遗传结构的相关数据。本研究旨在确定 ASD 在印度的遗传结构，并评估全外显子组测序（WES）作为遗传诊断的一线检测手段，而非染色体微阵列（CMA）。
2020 年至 2022 年间，共招募了 101 例原籍为印度的 ASD 患者-父母三体型。所有先证者均接受了包括核型分析、脆性 X 检测（仅在男性先证者中进行）、CMA 和 WES 的序贯遗传检测途径。采用正交方法进行候选变异验证和父母分离分析。
在 101 个三体型中，没有先证者被发现存在染色体异常或脆性 X。3（2.9%）和 30（29.7%）个三体型分别通过 CMA 和 WES 获得了明确的遗传诊断。在 WES 诊断中，SNVs 在 27 例（90%）中检测到，CNVs 在 3 例（10%）中检测到，包括从 CMA 中检测到的 3 个 CNVs。分离分析显示，66.6%（n=3 个 CNVs 和 n=17 个 SNVs）和 16.6%（n=5）的病例分别具有新生和隐性变异，这与非西班牙裔白人/欧洲血统 ASD 患者中观察到的变异类型和遗传模式分布一致。MECP2 基因是本队列中最常突变的基因（n=6；20%）。研究队列中确定的大多数受影响基因参与突触形成、转录及其调控、泛素化和染色质重塑。
本研究表明，新生变异是印度人群 ASD 的主要原因，雷特综合征是最常见的检测到的疾病。此外，我们提供了 CMA（3%）和 WES（30%）之间诊断收益显著差异的证据，支持在印度将 WES 作为 ASD 遗传诊断的一线检测手段。
