biostudies-literatureMa MNational Institute of Neurological Disorders and StrokeNational Institutes of Health Office of Research Infrastructure ProgramsNICHD NIH HHSInternational Rett Syndrome FoundationDoris Duke Charitable FoundationNIH Office of the DirectorNHGRI NIH HHSNINDS NIH HHSNational Human Genome Research InstituteNIH HHSNational Institute of Child Health and Human Development101125https://www.ebi.ac.uk/biostudies/studies/S-EPMC11335040biostudies-literatureUnknown26(7)<h4>Purpose</h4>YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.<h4>Methods</h4>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.<h4>Results</h4>Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrGenetics in medicine : official journal of the American College of Medical GeneticsHomozygous 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.PMC11335040UM1 HG006542R24 OD031447K23 NS125126R35 NS105078U54 HD083092R24 OD022005P50 HD105351P30 HD024064Tan KLMa MRosenfeld JATemel SGGanapathi MQuintanilla NSag SOChung WKLeDuc CAPereira EMHertel PMMcPartland AJLupski JRShen YHagen JPan XZheng YThomas CPCalame DGBove KEKanca OPehlivan DWangler MFLu SNguyen Galvan NTBellen HJfalseHomozygous 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.<h4>Purpose</h4>YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.<h4>Methods</h4>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.<h4>Results</h4>Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thr2024-01-01T00:00:00Z2024 Jul2026-06-02T13:13:09.238Z2026-04-18T03:11:05.812ZS-EPMC113350403852206810.1016/j.gim.2024.101125