Optimized trio genome sequencing (OTGS) as a first-tier genetic test in critically ill infants: practice in China

Rapid Phenotype-Driven Gene Sequencing with the NeoSeq Panel: A Diagnostic Tool for Critically Ill Newborns with Suspected Genetic Disease

“…The resulting diagnostic rate (13/33 patients [39.4%]) was comparable to that previously described for more extensive trio or singleton sequencing approaches, such as WES [16,21] and WGS [14,15,21,22], and even higher than that reported for WGS in NICU patients [20]. While higher diagnostic rates should be expected from WGS than WES, and from WES than CES or targeted panels, we found that the diagnostic rate does not correlate with the size of genome portion interrogated (Figure 1): NeoSeq provided diagnostic rates similar to those obtained with WGS and WES approaches, despite interrogating 10 times (WES) and 500 times (WGS) fewer bases.…”

“…Consequently, the phenotype of the newborn guides the analysis to a small group of candidate genes. Therefore, regardless of how extensive the genomic analysis, genetic diagnosis is limited to a shortlist of genes [14,21] and variant types [22]. Our results, and those of others using a similar approach [17], demonstrate that a simpler approach, based in the analysis of panels of genes with known functions and disease associations, can be a useful and more cost-effective alternative to WGS or WES approaches, yielding comparable diagnostic rates.…”

“…Nine were cohort studies, and three were randomized clinical trials. The selected studies applied the following sequencing techniques: CES (three studies) [12,13,17], WES (four studies) [16,18,19,23], WGS with subsequent filtering by CES (1 study) [14], WGS (three studies) [15,20,22], and WES + WGS (one study) [21]. The total number of patients included was 1073.…”

“…These results suggest that a diagnosis strategy based on the sequencing of a panel of genes associated with severe neonatal phenotypes yields better outcomes because those patients likely have a genetic disorder and can greatly benefit from accurate and early diagnosis. 14,15,20,22 , WES 16,18,19,23, and CES 12,13,17 ) showing the size of the genomic portion interrogated, the amount of data generated, and the median diagnostic rates achieved for each approach. To facilitate visual comparison, data are represented as the relative area of each circle.…”

“…Timely and specific diagnosis of newborns can have critical implications for health and wellbeing for the remainder of an infant's life. The few pilot studies focused on the use of this technology that have been conducted in NICU settings [12][13][14][15][16][17][18][19][20][21][22][23] have yielded highly promising results. Nonetheless, further advances in this field will be required to make precision, personalized, and predictive medicine a reality.…”