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. 2022 Sep;36(9):e24587.
doi: 10.1002/jcla.24587. Epub 2022 Jul 15.

Whole-exome sequencing identified five novel de novo variants in patients with unexplained intellectual disability

Wenqiu Zhang  1   2 , Li Hu  2 , Xinyi Huang  3 , Dan Xie  1   2 , Jiangfen Wu  1   2 , Xiaoling Fu  4 , Daiyi Liang  5 , Shengwen Huang  1   2   6
Affiliations

Whole-exome sequencing identified five novel de novo variants in patients with unexplained intellectual disability

Wenqiu Zhang et al. J Clin Lab Anal. 2022 Sep.

Abstract

Background: Intellectual disability (ID) represents a neurodevelopmental disorder, which is characterized by marked defects in the intellectual function and adaptive behavior, with an onset during the developmental period. ID is mainly caused by genetic factors, and it is extremely genetically heterogeneous. This study aims to identify the genetic cause of ID using trio-WES analysis.

Methods: We recruited four pediatric patients with unexplained ID from non-consanguineous families, who presented at the Department of Pediatrics, Guizhou Provincial People's Hospital. Whole-exome sequencing (WES) and Sanger sequencing validation were performed in the patients and their unaffected parents. Furthermore, conservative analysis and protein structural and functional prediction were performed on the identified pathogenic variants.

Results: We identified five novel de novo mutations from four known ID-causing genes in the four included patients, namely COL4A1 (c.2786T>A, p.V929D and c.2797G>A, p.G933S), TBR1 (c.1639_1640insCCCGCAGTCC, p.Y553Sfs*124), CHD7 (c.7013A>T, p.Q2338L), and TUBA1A (c.1350del, p.E450Dfs*34). These mutations were all predicted to be deleterious and were located at highly conserved domains that might affect the structure and function of these proteins.

Conclusion: Our findings contribute to expanding the mutational spectrum of ID-related genes and help to deepen the understanding of the genetic causes and heterogeneity of ID.

Keywords: de novo; heterogeneity; intellectual disability; variant; whole-exome sequencing.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Sanger sequencing and conservative analysis of COL4A1. (A) Sanger sequencing chromatograms show two de novo variants in patient 1. Black arrows refer to the mutations; (B) the positions p.V929 and p.G933 in the COL4A1 protein are highly conserved among nine species
FIGURE 2
FIGURE 2
Sanger sequencing, conservative and in silico analysis of TBR1. (A) Sanger sequencing chromatograms show a de novo variant in patient 2. The insertion fragment is within a red box; (B) the position p.Y553 residue in TBR1 is highly conserved among nine species; (C, D) the three‐dimensional structure prediction of the TBR1 WT and MUT proteins
FIGURE 3
FIGURE 3
Sanger sequencing, conservative and in silico analysis of CHD7. (A) Sanger sequencing chromatograms show a de novo variant in patient 3. The black arrow refers to the mutation; (B) the p.Q2338 residue is highly conserved among nine species; (C, D) the three‐dimensional structure prediction of the CHD7 WT and MUT protein; (E) the partial enlargement of the WT CHD7 protein; (F) the partial enlargement of the MUT CHD7 protein
FIGURE 4
FIGURE 4
Sanger sequencing, conservative and in silico analysis of TUBA1A. (A) Sanger sequencing chromatograms show a de novo variant in patient 4. The black arrow refers to the mutation; (B) the position p.E450 in TUBA1A is highly conserved among nine species; (C, D) the three‐dimensional structure prediction of the TUBA1A WT and MUT proteins
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