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Simple Summary  Gelsolin amyloidosis is a rare autosomal dominant genetic disease, which typically affects the cornea, skin and sometimes other organ systems and is caused by mutations in a gene coding for gelsolin protein ( GSN ). We describe a novel mutation of  GSN  gene, p.Glu580Lys, associated with gelsolin amyloidosis in six members of a two-generation family, who exhibited lattice corneal dystrophy, loose facial skin and irregular heart rhythm. In one patient we reported optic nerve impairment, which is possibly a novel feature associated with gelsolin amyloidosis.    Abstract  Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic  GSN  variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel  GSN  variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous  GSN  variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel GSN Variant p.Glu580Lys