Background: Most neonates undergoing CHD surgery have an appropriate adrenocortical stress response post-procedure. However abnormal cortisol and relative adrenal insufficiency can manifest with a relatively small subset of these infants as hemodynamic instability (4%), requiring fluid boluses, inotropic support and IV steroids with post-operative morbidity, and 2-17% incidence of mortality. Despite numerous studies, even via RCT, the cause for these differences in outcome is still unknown. As human biomarker evaluations are increasingly able to be rapidly completed, especially for specific genes, we sought to identify possible gene differences seen in neonates with post-cardiac surgery critical illness-related corticosteroid insufficiency (CIRCI).  

Methods: This study consisted of a single site, de-identified, retrospective, cross-section of term neonates who underwent CHD surgery from 8/2018 to 7/2020 and who had DNA-Seq performed per standard of care through our institution’s genome center. Chart review was completed for demographics, inotropic support, and cortisol levels. DNA-Seq analysis was completed utilizing Partek FLOW software, using Bowtie2 to align reads to hg38, and Partek Genotype likelihood algorithm to identify a list of aberrations for each individual with subsequent Clinical Insight (Qiagen) use for variant interpretation.  Expression of pulmonary hypertension, hypotension, and hemodynamic instability were used as filters.  

Results: Of 97 infants, 64 had cortisol levels drawn in the immediate post-operative period, and of these 16 had next-gene sequencing (NGS) panels performed. These 16 patients were then divided by cortisol level < 4.5mcg/dL (n=8, mean 2.28) and normal cortisol levels (n=8, mean 7.93). Demographics of the cohort of 16 patients included a median gestational age of 39 weeks, 10 days old at surgery, and hospital length of stay of 54.5 days; 81.3% male (n=13), 93.8% Caucasian (n=15), 18.8% Hispanic (n=3), and 81.3% having single ventricle CHD. DNA sequencing found that 100% of infants with CIRCI had the same genetic mutation found on the STX1A gene. STX1A is in the SNARE family which codes for the protein Syntaxin, responsible for fusion of synaptic vesicles with the presynaptic plasma membrane. This is accomplished by hydrolyzing ATP to create a conformational change in protein structure. In animal models, STX1A has been shown to have cardiac implications related to post-operative hemodynamic instability with cardiac dysfunction and excitation-contraction coupling through calcium channel kinetics (Virdi, 2019). STX1A is also in a critical deletion region of Williams-Beuren syndrome (Pierpoint, 2018).  

Conclusion: Potentially novel genetic abnormalities were seen in neonates with CIRCI within the STX1A gene. Future studies may include investigations for genetic abnormalities involving larger and multi-site cohorts beyond our single-site evaluation. Longer term potential aligns with the clinical development of a genetic biomarker panel to be performed prior to neonatal cardiac surgery to evaluate gene levels, and potential predisposition to the development of CIRCI and associated mortality and morbidity risk.