Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1

center dot PURPOSE: To report the genetic etiology of Lisch ep-ithelial corneal dystrophy (LECD). center dot DESIGN: Multicenter cohort study. center dot METHODS: A discovery cohort of 27 individuals with LECD from 17 families, including 7 affected members from the original LECD family, 6 patients from 2 new families and 14 simplex cases, was recruited. A cohort of 6 individuals carrying a pathogenic MCOLN1 (mu-colipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequenc- ing were used in all patients to identify pathogenic or likely pathogenic variants and penetrance of variants. RESULTS: Nine rare heterozygous MCOLN1 variants were identified in 23 of 27 affected individuals from 13 families. The truncating nature of 7 variants and functional testing of 1 missense variant indicated that they result in MCOLN1 haploinsufficiency. Importantly, in the homozygous and compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysoso- mal storage disorder mucolipidosis IV (MLIV). Auto- somal recessive MLIV is a systemic disease and com- prises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. However, the 6 parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype, suggesting MCOLN1 haploinsufficiency may be associated with reduced pene- trance and variable expressivity. CONCLUSIONS: MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlap- ping clinical features of corneal epithelial cells with autofluorescent inclusions reported in both LECD and MLIV, it is concluded that some carriers of MCOLN1 haploinsufficiency-causing variants present with LECD. (Am J Ophthalmol 2024;258: 183-195. (c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC li- cense (http://creativecommons.org/licenses/by-nc/4.0/))