Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants

Abstract

Background Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown. Methods RapSeq, a newly developed panel targeting 4,503 disease‐causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences. Results A diagnosis was made in 10/20 neonates (50%); eight had de novo variants ( ASXL1 , CHD , FBN1 , KMT2D , FANCB , FLNA , PAX3 ), one was a compound heterozygote for CHAT , and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control. Conclusions This study shows that a gene panel that includes the majority of known disease‐causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.

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

“…Phenomizer predicted a genetic diagnosis based on phenotype with statistical significance (p < 0.05) in only five patients. This rate of diagnosis prediction is similar to that reported by Brunelli et al [17] using a targeted gene panel (40%), and higher than that reported by French et al [20] (10%) using WGS. Based on their data, French et al proposed agnostic analysis of genomic data, as opposed to phenotype-driven analysis.…”

“…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. The second factor to consider is the association between the diagnostic rate and the severity of the clinical phenotype of the study participants.…”

“…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.…”