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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

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Ma, Mengqi
Ganapathi, Mythily
Zheng, Yiming
Tan, Kai-Li
Kanca, Oğuz
Bove, Kevin E.
Quintanilla, Norma
Sağ, Şebnem O.
Temel, Şehime G.
LeDuc, Charles A.

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Elsevier Science Inc

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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(KozakGAL4) 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). (c) 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

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Genetic-variation, Snare ykt6, Protein, Model, Pathogenicity, Transgenesis, Mechanism, Autophagy, Mutation, System, Autophagy, Drosophila, Failure to thrive, Fat body, Syrian christians of india, Genetics & heredity

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