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.

TitleHomozygous 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.
Publication TypeJournal Article
Year of Publication2024
AuthorsMa, M, Ganapathi, M, Zheng, Y, Tan, K-L, Kanca, O, Bove, KE, Quintanilla, N, Sag, SO, Temel, SG, LeDuc, CA, McPartland, AJ, Pereira, EM, Shen, Y, Hagen, J, Thomas, CP, Galván, NThao Nguye, Pan, X, Lu, S, Rosenfeld, JA, Calame, DG, Wangler, MF, Lupski, JR, Pehlivan, D, Hertel, PM, Chung, WK, Bellen, HJ
JournalGenet Med
Volume26
Issue7
Pagination101125
Date Published2024 Mar 21
ISSN1530-0366
Abstract

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 dYkt6 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).

DOI10.1016/j.gim.2024.101125
Alternate JournalGenet Med
PubMed ID38522068
Grant ListK23 NS125126 / NS / NINDS NIH HHS / United States