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

• DOI: 10.1016/j.gim.2024.101125
• Publication Date: 2024-03-21T23:46:13Z
• Authors: Mengqi Ma; Mythily Ganapathi; Yiming Zheng; Kai-Li Tan; Oguz Kanca; Kevin E. Bove; Norma Quintanilla; Sebnem O. Sag; Sehime G. Temel; Charles A. LeDuc; Amanda J. McPartland; Elaine M. Pereira; Yufeng Shen; Jacob Hagen; Christie P. Thomas; Nhu Thao Nguyen G...; Xueyang Pan; Shenzhao Lu; Jill A. Rosenfeld; Daniel G. Calame; Michael F. Wangler; James R. Lupski; Davut Pehlivan; Paula M. Hertel; Wendy K. Chung; Hugo J. Bellen
• Keywords: Male; Medical Sciences; Developmental Disabilities; Vesicular Transport Proteins; 610; Biomedical Informatics; Fat body; Loss of Function Mutation; Autophagy; Medical Specialties; Medicine and Health Sciences; Animals; Humans; Drosophila Proteins; and Immunity; Genetic Predisposition to Disease; Alleles; Biological Phenomena; Liver Diseases; Cell Phenomena; Carcinoma; Homozygote; Liver Neoplasms; Infant; Life Sciences; Hepatocellular; Genetics and Genomics; Failure to thrive; Syrian Christians of India; Phenotype; Medical Molecular Biology; Mutation; Female; Drosophila; Missense; Medical Genetics

YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.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.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.The YKT6 variants are partial loss-of-function alleles, and the p.(Tyr185Cys) is more severe than p.(Tyr64Cys).