SNARE-ing the reason for post-cardiac surgery critical illness-related corticosteroid insufficiency

Abstract

Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 to July 2020 at a Midwest freestanding children’s hospital. Of the 96 neonates who had cardiac surgery, for further inclusion, neonates had to have had both a cortisol level and next gene sequencing (NGS) drawn as a standard of care after cardiac surgery. Demographics and surgical outcomes were compared. Groups were defined by CIRCI with a cortisol level < 4.5 mcg/dL and non-CIRCI groups (level > 4.5 mcg/dL). DNA-Seq analysis was performed for each neonate in the DNA module of Partek FLOW software and filtered for confidence of mutations of 20 or above. Analysis excluded all common variants (detectable in more than 1% of the general population). Additionally, Bowtie2 was used to align reads to hg38 and Partek Genotype likelihood algorithm to identify a list of aberrations for each neonate. Those de-identified cohorted groups (CIRCI and non-CIRCI) were uploaded into Clinical Insight (Qiagen) for variant interpretation with biologic filters of pulmonary hypertension and hemodynamic instability. Neonates included in study analysis (n=16) demonstrated 206,409 variants which were then evaluated through biological filters. Similar types of cardiac diagnosis and surgeries were seen with trending rates of higher reintubation rate and longer lengths of stay within the CIRCI group. Seven gene mutations were found present in 75-100% of neonates with CIRCI (n=8) with 0-25% incidence of those corresponding mutations in neonates in the non-CIRCI group (n=8). CIRCI group had 100% incidence of heterozygous gene mutation on STX1A with splicing or loss of function with no findings of this mutation in the non-CIRCI group. Additional gene mutations were found in CIRCI group on RAB6A, ABCA3, SIDT2, and LILRB3 with no incidence in the non-CIRCI group. There were three additional mutations found across CIRCI 3Click here to enter text. group in INPPL1 and FAM189A2 (both splicing and missense) with 12-25% of patients in the non-CIRCI group also displaying these mutations. Novel genetic abnormalities were seen in neonates with symptoms of CIRCI with potential cardiac implications from gene mutation for STX1A. Additionally, compounding effects of the same patients having gene mutations on RAB6A, ABCA3, SIDT2, and LILRB3, INPPL1, and FAM189A2 need to be confirmed and explored for potential predisposition for hemodynamic instability during times of stress. Long-term potential aligns with the development of a genetic biomarker panel to be performed prior to neonatal cardiac surgery to identify genes predisposing neonates to the development of postoperative complications of CIRCI.