Current application of next-generation sequencing (NGS) leads to detection of the underlying disease-causing gene and mutation or mutations in from 60% to 85% of patients with inherited retinal diseases (IRDs), depending on the methods used, disease type, and population tested. In a cohort of 320 families with autosomal dominant retinitis pigmentosa (adRP), we have detected the mutation in 82% of cases using a variety of methods, leaving more than 50 families with “elusive” disease genotypes. All of the remaining families have been screened for mutations in known IRD genes using retinal-targeted-capture NGS, and most have been tested by whole-exome NGS. Linkage mapping has been conducted in several large families. In one of these families, with DNA samples from ten affected family members and six unaffected, linking members, we observed substantial maximum two-point LOD scores for linkage to both chromosomes 2 and 4. Subsequent 10X Genomics Chromium™ sequencing, which facilitates linked-read, phase-known chromosomal analysis, revealed a balanced translocation of the q terminus arms of chromosomes 2 and 4 involving 35 Mb and 73 Mb of 2 and 4, respectively. The balanced translocation is present in all affected family members and absent from all unaffected individuals. Family histories suggest multiple miscarriages are associated with the translocation. The breakpoint on chromosome 4 is within or 5′ to the LRAT gene, whereas the chromosome 2 break is in a gene-poor region. We conclude that the balanced translocation is the cause of adRP in this family, which may lead to dysregulation of the LRAT gene. Since multiple miscarriages are a hallmark of balanced translocations, this possibility should be considered in evaluating family histories. Further, large structural variants, which are not easily detected by conventional sequencing methods, may account for a significant fraction of the remaining unsolved families.