Researchers have identified a rare genetic variant responsible for Marfan syndrome in two domestic cats, providing new insights into the molecular mechanisms of a connective tissue disorder that is more commonly seen in humans.
The study, published in Scientific Reports, describes two male littermates, Gary and Shaggy, with characteristic features of Marfan syndrome, including displaced eye lenses, unusually long limbs, and severe enlargement of the aorta. While the condition affects about 1 in 4,000 people, this was the first known documented case in cats.
Marfan syndrome is typically caused by variants in FBN1, a gene responsible for producing fibrillin-1, a protein that helps maintain the strength and elasticity of connective tissues. The condition can affect the eyes, skeleton, and cardiovascular system.
Whole-genome sequencing identified the same rare FBN1 variant in both cats. The variant was absent from genomic data representing more than 1,000 other cats, suggesting it was specific to the affected family. Although both animals inherited two copies of the variant, further investigation revealed that it did not completely disable the gene.
Using long-read RNA sequencing, the researchers discovered that approximately 73 percent of the affected cat's FBN1 transcripts were missing exon 22, a section of genetic information important for producing a stable protein. The remaining transcripts retained this section, potentially allowing some normal fibrillin-1 production. That remaining function helps explain why Gary and Shaggy were able to survive into adulthood, when harboring two copies of such a mutation would usually result in a much more severe form of the disorder.
The findings demonstrate why DNA sequencing alone may be insufficient to establish whether a genetic variant causes disease. Functional RNA analysis can reveal molecular abnormalities that conventional variant prediction overlooks.
The authors acknowledge that the findings are limited to two related animals, with no direct analysis of fibrillin-1 protein production. Nevertheless, the research illustrates the value of combining clinical findings, tissue pathology, genomic sequencing, and RNA analysis to establish the consequences of rare genetic variants.
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