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

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 Galván
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

Publication Date

7-1-2024

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2024.101125

PMID

38522068

PMCID

PMC11335040

PubMedCentral® Posted Date

1-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Female, Humans, Infant, Male, Alleles, Carcinoma, Hepatocellular, Developmental Disabilities, Drosophila, Drosophila Proteins, Genetic Predisposition to Disease, Homozygote, Liver Diseases, Liver Neoplasms, Loss of Function Mutation, Mutation, Missense, Phenotype, Vesicular Transport Proteins, Autophagy, Drosophila, Failure to thrive, Fat body, Syrian Christians of India

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

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).

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