Researchers at Baylor College of Medicine and Boston Children’s Hospital have identified a rare genetic variant in the YKT6 gene that appears to trigger a previously uncharacterized neurological syndrome. The discovery, described in Genetics in Medicine, points to developmental delays alongside impaired liver function in affected individuals, marking a new intersection of neurology and hepatic biology tied to this gene.
The study followed three unrelated children in the United States who displayed early developmental challenges affecting thinking abilities, memory, and attention. In two of these cases, liver dysfunction was also present, raising concerns about broader health risks, including a potential susceptibility to cancer. Through whole-genome sequencing, researchers found that rare alterations in YKT6 were linked to the simultaneous neurological and hepatic abnormalities observed in these children.
Prior to this work, YKT6 had not been associated with disease caused by genetic mutations. To uncover how YKT6 variants could drive the observed pathology, the team studied the fruit fly equivalent of the gene. The results suggested a conserved mechanism that transcends species, offering a window into how these variants disrupt normal cellular operations.
The investigators demonstrated that unusual YKT6 variants impair autophagy, a vital cellular housekeeping process. In mammals, YKT6 participates in the fusion of autophagosomes with lysosomes to form autolysosomes. This fusion is essential for degrading and recycling surplus or damaged proteins, lipids, and other cellular components, thereby maintaining cellular health and function. When autophagy is compromised, cellular waste can accumulate, potentially driving dysfunction in specialized tissues such as the brain and liver.
As the study explains, impaired clearance of cellular debris stemming from YKT6 variants can disrupt protein processing and organelle maintenance. The consequence is a buildup of dysfunctional proteins and waste products that correlate with neurodevelopmental delays and declining liver performance. The work emphasizes how a single gene can influence multiple organ systems through a shared cellular pathway, underscoring the interconnected nature of genetic disorders and the importance of examining gene function across tissues to fully understand clinical outcomes.
In the broader context, this research adds to a growing body of evidence that autophagy-related genes contribute to neurological health and hepatic stability. The findings invite further exploration into targeted therapies that could bolster autophagic flux or compensate for YKT6-related defects, offering hope for future interventions that may mitigate disease progression in affected individuals. The study also highlights the value of cross-species analyses in uncovering conserved genetic mechanisms that shape human disease and points to new avenues for diagnostics and personalized medicine as scientists continue to map the effects of YKT6 variants across diverse populations.