Abstract
Objective
The context was designed to optimize the diagnostic utility of clinically focused exome sequencing (CFES) and shorten the diagnostic odyssey among pediatric patients suspected of monogenic disorders (MDs).
Methods
Here, we retrospectively analyzed the clinical notes of 372 patients from different areas in the Jiangxi province that were referred for a diagnostic CFES and analysis from June 2018 to March 2022 with symptoms suggestive of MDs. In our study, preliminary tests using the proband-only clinical exome sequencing as a cost-effective first-tier diagnostic test for pediatric patients with unidentified MDs, supplemented by family segregation studies for targeted variants when indicated.
Results
Probands with confirmed diagnostic (CD) or likely diagnostic (LD) genetic influences accounted for 12% of all cases, whereas those with an uncertain diagnosis accounted for 48%. We also found that systemic primary carnitine deficiency (CDSP) (SLC22A5 gene) and phenylketonuria (PAH gene) were relatively more prevalent, and these patients with CDSP had the most frequent c.1400C > G variant (p.S467C) and c.51C > G variant (p. F17L) in this study. In addition, statistical analysis revealed that the estimates of diagnostic yields varied across certain phenotypic features of patients, and patients with specific phenotypic traits tended to benefit more from CFES.
Conclusion
The CFES may be a first-line genetic test for diagnosing young children with suspected genetic conditions, as it validates the identification of molecular genetics alterations and facilitates comprehensive medical management. Moreover, we found that infants exhibiting metabolism/homeostasis abnormalities, craniofacial /otolaryngology/ ophthalmologic abnormalities, and/or the integument were significantly more likely to receive a genetic diagnosis via CFES than infants without such features. However, due to the current study’s low diagnostic yield and inherent limitations, high-quality clinical studies with larger sample sizes are still needed to provide more likely results and confirm our findings.
Declaration
This study complies with the Declaration of Helsinki.
Data Sharing Statement
The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.
Disclosure
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.