Abstract
To identify next-generation-sequencing (NGS) clinical usability and to propose a standard diagnostic routine for critically ill infants, aged less than 100 days and suspected of having a genetically heterogeneous condition, a retrospective study was conducted between January 2016 and December 2018 at neonatal intensive care units (NICUs) of three tertiary hospitals in Shanghai, China. Whole-exome sequencing (WES) or panel sequencing was performed on 307 patients. Trio-WES, trio-panel, proband-WES, and proband-panel diagnostic yields were 39.71% (83/209), 68.75% (22/32), 59.09% (26/44), and 33.33% (4/12), respectively. Definitive molecular diagnoses of 142 infants (46.25%) uncovered 99 disorders; 21 disorders displayed on 44.37% of the diagnosed patients. Genetic etiologies were identified for 61.73% (50/81) of the deceased infants. One in three (29.58%) diagnosed infants exhibited one of the following four clinical traits which had a higher odds of diagnostic rate: integument abnormality (adjusted odds ratio [aOR], 19.7; 95% confidence interval [CI], 2.5–156.3), complex immune-related phenotypes (aOR, 9.2; 95% CI, 1.4–83.5), mixed nervous system phenotypes and congenital anomalies (aOR, 5.0; 95% CI, 1.3–19.1), or mixed metabolism and nervous system phenotypes (aOR, 4.5; 95% CI, 1.0–21.5). Our results demonstrated that NGS was an effective diagnostic tool. Infants exhibiting integument, complex immune-related conditions, metabolism, and nervous signs have higher chances of carrying variants in known disease-causing genes. The number of specific phenotypes could be used as an independent predictor of a positive molecular diagnosis, rather than an isolated abnormality. We developed a molecular diagnostic procedure for the use of NGS for diagnosis in Chinese NICU population based on individual characteristics.
Highlights
With improvements in health care, genetic diseases have become the leading causes of infant mortality in neonatal intensive care units (NICUs) (Jacob et al, 2015)
Subgroup analysis revealed no significant difference between two inclusion scenarios for molecular diagnosis rate (44.21% vs. 47.17%, P = 0.631) and 180d mortality (29.47% vs. 25.00%, P = 0.411) (Supplementary Table S3)
Provided the main clinical indications for the NGS requests aforementioned, further robust investigation is warranted to assess whether specific clinical presentation were more likely to be associated with a molecular diagnosis (Table 2 and Supplementary Methods, Supplementary Tables S4 and S5)
Summary
With improvements in health care, genetic diseases have become the leading causes of infant mortality in neonatal intensive care units (NICUs) (Jacob et al, 2015). Several studies in Caucasian populations regarding the application of NGS in NICUs were reported (Daoud et al, 2016; Meng et al, 2017; French et al, 2019; Gubbels et al, 2019) These studies reached seemingly contradictory statements, some suggesting phenotype-driven selection (Gubbels et al, 2019) and the others in favor of a first-line strategy as a determiner in NGS assays (Stark et al, 2016; French et al, 2019). This controversy was primarily due to between-study heterogeneity depending on the country or region where the genetic studies are performed and overlapping clinical manifestations of genetic and non-genetic causes in neonatal/early infant period (Pogue et al, 2018)
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