Abstracts

Rationale: To investigate the underlying genetic diagnosis of a patient with dysmorphic features and multi-organ dysfunction including microcephaly, epilepsy with infantile spasms, cardiac, renal, and bone involvement, with abnormal transferrin electrophoresis. Methods: Patient, parents, and sibling had clinical exome sequencing (GeneDx Laboratory) and carbohydrate deficient transferrin studies (Mayo Clinic Laboratory). Results: Exome Sequencing (ES) revealed three homozygous Variants of Uncertain Significance (VUS): 1) GLUL c.857G>A (p.R286H) 2) XYLT2c.611G>A (p.R204Q) 3) OSTC c.431+1G>A (IVS3+1G>A). All variants were heterozygous in the parents. Quad ES revealed the proband’s asymptomatic older sibling was also homozygous for the GLUL c.857G>A (p.R286H) and the XYLT2 c.611G>A (p.R204Q) variants, but did not carry the OSTC c.431+1G>A variant. This variant is predicted to destroy the canonical splice donor site in intron 3 and therefore result in abnormal splicing and most likely premature truncation of the protein. Homozygous loss-of-function variants have not been seen in large population databases including the gnomAD, TopMED, and Iranome datasets. Results of carbohydrate deficient transferrin studies were consistent with a congenital disorder of glycosylation (CDG) type 1. Of note, the proband did not have any evidence of liver disease.   Conclusions: Given the compelling genetic and clinical data, we propose that the homozygous loss-of-function OSTC variant represents a novel congenital disorder of glycosylation, OSTC-CDG, with multi-organ dysfunction. This includes microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, and skeletal dysplasia with extreme short stature. OSTC variants should be considered as part of the differential diagnosis when carbohydrate deficient transferrin is abnormal and/or when a CDG is suspected. Funding: No funding