Genetic Analysis of Children With Unexplained Developmental Delay and/or Intellectual Disability by Whole-Exome Sequencing.

Jingjing Xiang,Ting Wang,Hui Tang,Fei Yang,Ang Gao,Jun Mao,Wei Zhang,Yang Ding,Quanze He,Qin Zhang

doi:10.3389/fgene.2021.738561

Jingjing Xiang, Ting Wang + Show 8 more

Open Access

https://doi.org/10.3389/fgene.2021.738561

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Abstract

Background: Whole-exome sequencing (WES) has been recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders (NDDs). We aimed to identify the genetic causes of 17 children with developmental delay (DD) and/or intellectual disability (ID). Methods: WES and exome-based copy number variation (CNV) analysis were performed for 17 patients with unexplained DD/ID. Results: Single-nucleotide variant (SNV)/small insertion or deletion (Indel) analysis and exome-based CNV calling yielded an overall diagnostic rate of 58.8% (10/17), of which diagnostic SNVs/Indels accounted for 41.2% (7/17) and diagnostic CNVs accounted for 17.6% (3/17). Conclusion: Our findings expand the known mutation spectrum of genes related to DD/ID and indicate that exome-based CNV analysis could improve the diagnostic yield of patients with DD/ID.

Highlights

Whole-exome sequencing (WES) has been recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders (NDDs)
WES is recommended as a first-tier clinical diagnostic test for individuals with NDDs with an overall diagnostic yield of 36%, including 31% for isolated NDD, and 53% for NDD plus associated conditions, which is greater than the diagnostic yield of CMA (15%–20%) (Srivastava et al, 2019)
Analysis of WES data revealed that the coverage for over 97% of the targeted bases were over 20×, with an average sequencing depth of over 100×

Summary

Introduction

Whole-exome sequencing (WES) has been recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders (NDDs). We aimed to identify the genetic causes of 17 children with developmental delay (DD) and/or intellectual disability (ID). Developmental delay (DD) and intellectual disability (ID) are major manifestations of neurodevelopmental disorders (NDDs) with a global prevalence of 1%–3% (Thapar et al, 2017; Ismail and Shapiro, 2019). Chromosomal microarray has been recommended as a first-tier clinical test to identify chromosomal CNVs and regions of homozygosity in individuals with DD/ID, autism spectrum disorders (ASDs), or multiple congenital anomalies with a diagnostic yield of 15%–20% (Manning et al, 2010; Miller et al, 2010).

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