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. 2022 Sep 2:13:967688.
doi: 10.3389/fgene.2022.967688. eCollection 2022.

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

Jieyi Chen  1   2   3 , Ping Zhang  4 , Meifang Peng  5 , Bo Liu  4 , Xiao Wang  4 , Siyuan Du  3 , Yao Lu  6 , Xiongzheng Mu  1 , Yulan Lu  4 , Sijia Wang  3 , Yingzhi Wu  1
Affiliations

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

Jieyi Chen et al. Front Genet. .

Abstract

Craniosynostosis (CRS) is a disease with prematurely fused cranial sutures. In the last decade, the whole-exome sequencing (WES) was widely used in Caucasian populations. The WES largely contributed in genetic diagnosis and exploration on new genetic mechanisms of CRS. In this study, we enrolled 264 CRS patients in China. After a 17-gene-panel sequencing designed in the previous study, 139 patients were identified with pathogenic/likely pathogenic (P/LP) variants according to the ACMG guideline as positive genetic diagnosis. WES was then performed on 102 patients with negative genetic diagnosis by panel. Ten P/LP variants were additionally identified in ten patients, increasing the genetic diagnostic yield by 3.8% (10/264). The novel variants in ANKH, H1-4, EIF5A, SOX6, and ARID1B expanded the mutation spectra of CRS. Then we designed a compatible research pipeline (RP) for further exploration. The RP could detect all seven P/LP SNVs and InDels identified above, in addition to 15 candidate variants found in 13 patients with worthy of further study. In sum, the 17-gene panel and WES identified positive genetic diagnosis for 56.4% patients (149/264) in 16 genes. At last, in our estimation, the genetic testing strategy of "Panel-first" saves 24.3% of the cost compared with "WES only", suggesting the "Panel-first" is an economical strategy.

Keywords: candidate variants; cost estimation; craniosynostosis; genetic diagnosis; research pipeline; whole-exome sequencing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The framework of the whole study. Analyses on the genetic diagnosis and variants identification are in single solid line box. Analysis on the economic cost is in double solid line box.
FIGURE 2
FIGURE 2
Situation of clinical diagnosis, genetic diagnosis and pathogenic genes of craniosynostosis in the Chinese cohort of this study (n = 264). The pie chart on the left shows a broad classification based on clinical diagnosis and genetic diagnosis in this study. The pie chart on the left shows the diagnosis contribution of 16 pathogenic genes in positive genetic diagnosis.
See this image and copyright information in PMC

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