Novel pathogenic variant in the LCAT gene in a compound heterozygous patient with fish-eye disease and a mild...

Low high-density lipoprotein (HDL)-cholesterol and corneal opacity are associated with fish-eye disease (FED), familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), apolipoprotein AI deficiency, and Tangier disease. The differential diagnosis is made by clinical and biochemical tests. Measuring the LCAT activity is the ideal way to distinguish conditions caused by LCAT gene variants (FED and FLD) from the other 2 diseases. However, this is not accessible from all clinics. The cholesteryl ester/total cholesterol (CE/TC) ratio, which is below the reference range in most cases with LCAT gene variants, has been proposed as an alternative. We report a case of compound heterozygous FED with a CE/TC ratio within the reference range.

LCAT activity assays and genetic analyses were performed using patients' blood samples. Identified LCAT gene variants were examined by an in vitro expression assay.

The proband showed approximately 20% LCAT α-activity relative to the normolipidemic controls, whereas a patient with a typical FED-causing variant (p.Thr147Ile) showed only 3% activity. We identified compound heterozygous variants (c.101C > T/c.460A > G) resulting in a p.Pro34Leu/p.Asn154Asp amino acid residue substitution in the LCAT gene of the proband. The former variant has been reported previously, but the latter was newly identified. An in vitro expression assay demonstrated that the LCAT α-activity of the p.Asn154Asp variant significantly decreased regarding the wild type, but it was relatively well preserved compared to the typical FED-causing variants (p.Pro34Leu and p.Thr147Ile).

These results suggest that the residual 20% LCAT α-activity is sufficient to normalize CE/TC, but not sufficient to prevent the development of corneal opacity in FED.