US: A recent joint investigation identified uncommon mutations in the YKT6 gene as the source of a novel neurological illness characterised by developmental delays, severe progressive liver disease, and a risk of liver cancer.
The study, published in genetics">Genetics in Medicine, was 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), and Dr Wendy Chung, Chief of Paediatrics at Boston Children's Hospital.
"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," Dr. Bellen said.
"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."
YKT6 gene variants disrupt brain development and sometimes, liver function In collaboration with Dr Mythily Ganapathi at Columbia University Irving Medical Center, Drs. Paula Hertel and Davut Pehlivan at Texas Children's Hospital and Dr. James Lupski at Baylor College of Medicine, and by using the GeneMatcher tool and Baylor genetics">Genetics clinical diagnostics laboratory, this team of researchers and clinicians found three unrelated individuals with missense (analogous to misspellings in a word) variants in both copies of the YKT6 gene.
All three individuals had early onset of disease (four to six months of age) with failure to thrive. Two of them had an identical missense variant because of which the tyrosine amino acid at position 185 was changed to cysteine (Tyr185Cys).
On the other hand, the third child carried a variant that caused the same amino acid change but in a different location (Tyr64Cys) of the YKT6 protein. Interestingly, in addition to developmental delays and neurological defects which were observed in all three children, only the two individuals with the Tyr185Cys variant had liver dysfunction and a potential risk for developing liver cancer.
"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," Dr Mythily Ganapathi said.
"Our genetic lineage analysis suggests this variant likely originated from a common ancestor before the community split."
YKT6 gene variants impair autophagy
"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," Dr Bellen added.
