Targeted sequencing with single-molecule molecular inversion probes highlights a gap in understanding the cause of Fuchs endothelial corneal dystrophy.

Purpose: A trinucleotide repeat expansion in Methods: Genomic DNA from blood was genotyped for expansion of the CTG18.1 repeat in intron 2 of Results: Analysis of 114 FECD cases by STR/TP-PCR stratified the patients into FECD expansion-negative cases that had <50 trinucleotide repeats on both alleles at the CTG18.1 locus (n = 33 probands and three additional family members) and FECD expansion-positive (n = 78) cases with at least one allele harboring ≥50 repeats in size. All 36 expansion negative cases were then analyzed by smMIP targeted capture and short-read sequencing of the five other genes implicated in FECD causation. For comparison, two control groups were similarly analyzed: a subset of 29 of the expansion-positive cases whose FECD was assumed to be caused by the repeat expansion and 29 expansion-negative unaffected individuals. Across all groups, 13 variants passed filtration criteria: 1 in Conclusions: smMIPs were used for targeted screening of candidate genes implicated in FECD and proved a versatile, economic approach for prescreening before whole-exome or genome sequencing. This study confirmed the well-documented enrichment of the