Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma.

PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases. METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6KozakGAL4 allele to assess the expression pattern of dYkt6. RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, developmental delay, and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual is homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] and exhibited neurodevelopmental disorders and optic atrophy. Fly dYkt6 is essential and is expressed in the fat body (analogous to liver) and central nervous system. Wild-type genomic rescue constructs can rescue the lethality and autophagic flux defects, whereas the variants are less efficient in rescuing the phenotypes. CONCLUSION: The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).

Donor Gamma-Glutamyl Transferase Is Associated With Liver Allograft Discard and Failure.

INTRODUCTION: The disparity between the number of individuals on the wait list and available liver allografts creates the need for a system that maximizes donor liver utilization and predicts graft failure. RESEARCH QUESTION: This study aimed to determine the relationship between donor Gamma-Glutamyl Transferase (GGT), liver discard, and graft failure. DESIGN: Through multivariate analysis from 53 966 deceased liver donors, we adjusted for donor clinical and demographic characteristics and compared donor GGT with allograft discard. We compared donor GGT ranges with graft failure and analyzed data from 47 269 liver recipients. RESULTS: After adjusting for other factors, donor GGT was significantly associated with liver discard, with GGT over 200 U/L being most significant (OR 2.74, CI 2.51-2.99). Donor GGT under 20 U/L was also found to be a protective factor for post-transplant graft failure (HR 0.91, CI 0.83 - 1.00). CONCLUSION: Going forward, GGT should be included among other characteristics associated with allograft discard considered during the procurement process.