Joint Study Shows YKT6 Gene Variants May Cause Novel Genetic Disorders

A groundbreaking joint investigation pinpointed rare mutations in the YKT6 gene as the root cause of an unprecedented neurological disorder characterized by developmental delays, progressive liver disease, and an increased risk of liver cancer.

Led by Dr. Hugo Bellen, Distinguished Service Professor at Baylor College of Medicine and Principal Investigator at Texas Children's Hospital's Jan and Dan Duncan Neurological Research Institute (Duncan NRI), alongside Dr. Wendy Chung, Chief of Pediatrics at Boston Children's Hospital, the study has been published in Genetics in Medicine.

Dr. Bellen highlighted the significance of their findings, stating, "It is known that the YKT6 gene plays important roles in many intracellular vesicular trafficking events in the cells but this is the first time it has been linked to a genetically inherited disorder. This study, using patient samples and fruit flies, provides a solid experimental foundation for future studies to better understand this new disease and to develop therapies."

The investigation, which involved collaboration with experts including Dr. Mythily Ganapathi at Columbia University Irving Medical Center and Drs. Paula Hertel and Davut Pehlivan at Texas Children's Hospital, identified three unrelated individuals with missense variants in both copies of the YKT6 gene.

Dr. Mythily Ganapathi noted the unique genetic lineage of the affected individuals, stating, "Interestingly, both individuals with the Tyr185Cys variant belong to the Syrian/Saint Thomas Christians of Kerala, India, a group currently estimated to be comprised of about 5 million individuals worldwide."

The study revealed that YKT6 gene variants disrupt brain development and, in some cases, liver function, with specific variants linked to differing severity of symptoms. Dr. Paula Hertel emphasized the importance of genetic screening, stating, "Our work suggests children diagnosed with YKT6 liver disease will also need to be screened for hepatocellular carcinoma."

Further investigations into the biological mechanisms behind these variants demonstrated their impact on autophagy, a critical cellular process. Dr. Mengqi Ma, a postdoctoral fellow in the Bellen lab, explained, "Our results showed that the fly Ykt6 Tyr186Cys cause more severe defects than Tyr65Cys, suggesting that the corresponding human YKT6 Tyr185Cys is a more severe variant than Tyr64Cys."

Dr. Bellen concluded, "In summary, we have discovered YKT6 variants as the cause of a novel developmental disorder affecting brain function and in certain cases, also liver function, providing us valuable insights into a new genetic disease. However, additional studies with more patients will be needed to precisely understand the pathogenesis and to identify potential therapeutic targets for this condition."

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