(1058) Whole Genome Sequencing Identifies RYR1 Variant Contributing to Multisystem Organ Failure in DKA

Introduction: Whole genome sequencing (WGS) is quickly becoming part of the intensivist’s arsenal, especially when conventional means are inconclusive or prolonged. This case highlights the utility of WGS in unmasking causes of severe manifestations of common ICU disorders.

Description: A 13 yo F was admitted to the PICU with severe new onset DKA and septic shock. She had an initial pH of 6.8 and showed signs of cerebral edema and increased intracranial pressure with bradycardia, hypertension, and significantly altered mental status that was refractory to hyperosmolar therapy. Despite initiation of a DKA protocol and electrolyte replacement, her acidosis persisted with a nadir of 6.6 and developed electrolyte abnormalities with dysrhythmias. She required intubation for airway protection and a sodium bicarbonate infusion was started to improve her dysrhythmia. In the following days the patient continued to deteriorate. She developed rhabdomyolysis with peak creatine kinase of more than 280,000 U/L along with significant transaminitis. She required multiple blood product transfusions for disseminated intravascular coagulation and CT imaging of her brain showed associated intraparenchymal bleeds. She progressed to anuric renal failure requiring continuous renal replacement therapy. Given the degree of her presentation she was enrolled in a WGS study to further elucidate underlying causes of her presentation. WGS revealed a paternally inherited, heterozygous, pathogenic variant in the RYR1 gene; which is consistent with susceptibility to Malignant Hyperthermia (MHS1). This diagnostic result was advantageous in coordinating her care, including anesthetic considerations for placement and removal of her long-term hemodialysis catheter, gastrostomy tube and tracheostomy. She is currently recovering in a rehabilitation facility, where she is not ventilator or dialysis dependent.

Discussion: This case illustrates the utility of WGS as a diagnostic tool in critically ill children for finding contributory causes to severe presentations of classic ICU disorders. The identification of the RYR1 variant facilitated a change in her anesthetic approach to decrease her risk of malignant hyperthermia. With more widespread application in the future, WGS holds incredible promise for precision medicine for our patients.