Atypical Presentation of -Related Disorder: Expanding the Phenotype and Genotype.

Aminoacyl-tRNA synthetases (ARSs) catalyze the formation of aminoacyl-tRNA, which is required for protein translation. A growing number of cases are associated with ARS deficiencies. Pathogenic variants in (MIM# 600709), encoding cytoplasmic isoleucyl-tRNA synthetase, have been associated with autosomal recessive growth retardation, impaired intellectual development, hypotonia, and hepatopathy (GRIDHH, OMIM# 617093). To date, 11 GRIDHH patients have been described. We identified a patient who presented with recurrent episodes of liver failure in the setting of preceding infection and neurocognitive delay, and who recently presented with a clinical picture consistent with chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis. Exome sequencing revealed that this patient is compound heterozygous for two variants: c.1193dupC;p.(Cys400LeufsTer32) and c.746A>G;p.(Asp249Gly). The frameshift variant is predicted to cause a loss of function, and functional analysis of the p.Asp249Gly variant was performed using baker's yeast. Wild-type human has been shown to support robust yeast growth in the absence of the yeast ortholog, , while human harboring p.Asp249Gly could not, indicating a loss-of-function effect. The proband was treated with isoleucine supplementation with subjective clinical improvement. Overall, we expand the molecular and clinical spectra of the -related disorder, highlight immune dysregulation as a possible novel manifestation of this disorder, and emphasize the utility of a yeast model system for functional studies. A larger cohort of patients is required to validate these observations and evaluate the efficacy of isoleucine supplementation for patients with GRIDHH.