A homozygous hypomorphic FBN1 splice region variant in domestic cats with Marfan syndrome

Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disease caused by variants in the fibrillin 1 ( FBN1 ) gene. While common in humans, spontaneous animal models are rarely reported. We present the first phenotypic and molecular characterization of MFS in domestic cats. A pair of random-bred littermates exhibited bilateral lens luxation and aortic root dilation, the cardinal features of MFS, as well as long limbs. Histopathology of the ascending aorta from an affected cat revealed disrupted and fractured elastic fiber tendrils, consistent with impaired fibrillin-1 function and the medial degeneration seen in human MFS. Whole genome sequencing identified a homozygous variant at a conserved nucleotide 3 base-pairs upstream of FBN1 exon 22 (XM_023255387.2:c.2678-3C > A) that was absent in a cohort of over 1000 cats. The impact on splicing was assessed via Oxford Nanopore sequencing of cDNA from an affected cat. This revealed exon 22 skipping in 73% of transcripts, affecting the second hybrid domain which is important for protein folding and stability. Despite possessing the variant in homozygosity, the cats were functionally heterozygous due to a leaky splice site that produced low levels of normal transcript. These results provide comparative insight into the genetic and molecular basis of MFS.