Title | 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. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Ma, 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 |
Journal | Genet Med |
Pagination | 101125 |
Date Published | 2024 Mar 21 |
ISSN | 1530-0366 |
Abstract | PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases. METHODS: We report three 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 (GRs) 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 GR 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). |
DOI | 10.1016/j.gim.2024.101125 |
Alternate Journal | Genet Med |
PubMed ID | 38522068 |
Grant List | K23 NS125126 / NS / NINDS NIH HHS / United States |