PURPOSE: To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). DESIGN: Multicenter cohort study. 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 (mucolipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequencing 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 lysosomal storage disorder mucolipidosis IV (MLIV). Autosomal recessive MLIV is a systemic disease and comprises 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 penetrance and variable expressivity. CONCLUSIONS: MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlapping 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.

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami USA

Department of Ophthalmology Stein Eye Institute David Geffen School of Medicine UCLA Los Angeles CA 90095 USA

Department of Ophthalmology University Medical Center of the Johannes Gutenberg University Mainz 55131 Mainz Germany

Department of Pediatrics 1 Medical University of Innsbruck 6020 Innsbruck Austria

Department of Pediatrics and Brotman Baty Institute for Precision Medicine University of Washington Seattle WA 98195 USA

From the Department of Genome Sciences University of Washington Seattle WA 98195 USA

Genetic Institute Tel Aviv Sourasky Medical Center Tel Aviv 6423906 Israel

Genetic Unit Sieff hospital Bar Ilan University Faculty of Medicine Safed Israel

Independent scholar N Jespersensvej 3 DK 2000 Copenhagen Frederiksberg Denmark

Moorfields eye hospital NHS foundation trust London UK

Ophthalmology unit Maccabi and Clalit Health Services Magdal Shams Medical center Golan Heights Israel

Pediatric Metabolic Clinic Sieff hospital Bar Ilan University Faculty of Medicine Safed Israel

Tennent Institute of Ophthalmology NHS Greater Glasgow and Clyde Gartnavel General Hospital 1053 Great Western Road Glasgow G12 0YN UK

UCL Institute of Ophthalmology 11 43 Bath Street London EC1V 9EL UK

Universitäts Augenklinik Elfriede Aulhorn Str 7 72076 Tübingen Deutschland

References provided by Crossref.org

Genotype-Phenotype Correlations in Corneal Dystrophies: Advances in Molecular Genetics and Therapeutic Insights