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Abstract Background Whole exome sequencing (WES) allows for an unbiased search of the genetic cause of a disease. Employing it as a first-tier genetic testing can be favored due to the associated lower incremental cost per diagnosis compared to when using it later in the diagnostic pathway. However, there are technical limitations of WES that can lead to inaccurate negative variant callings. Our study presents these limitations through a re-evaluation of negative WES results using subsequent tests primarily driven by fundoscopic findings. These tests included targeted gene testing, inherited retinal gene panels, whole genome sequencing (WGS), and array comparative genomic hybridization. Results Subsequent genetic testing guided by fundoscopy findings identified the following variant types causing retinitis pigmentosa that were not detected by WES: frameshift deletion and nonsense variants in the RPGR gene, 353-bp Alu repeat insertions in the MAK gene, and large exonic deletion variants in the EYS and PRPF31 genes. Deep intronic variants in the ABCA4 gene causing Stargardt disease and the GUCY2D gene causing Leber congenital amaurosis were also identified. Conclusions Negative WES analyses inconsistent with the phenotype should raise clinical suspicion. Subsequent genetic testing may detect genetic variants missed by WES and can make patients eligible for gene replacement therapy and upcoming clinical trials. When phenotypic findings support a genetic etiology, negative WES results should be followed by targeted gene sequencing, array based approach or whole genome sequencing.

Abstract Background SLIT2 is a protein ligand for the Roundabout (ROBO) receptor and was found to play a major role in repulsive midline axon guidance in central nervous system development. Based on studies utilizing knockout models, it has been postulated that SLIT2 is important for preventing inappropriate axonal routing during mammalian optic chiasm development. Methods Case report. Results Here, we report a case of congenital myopia, anisometropia, and obesity in a patient with a SLIT2 point mutation. Examination of the patient’s skin biopsy revealed abnormalities in elastin and collagen fibrils that suggest an underlying connective tissue disorder. Structural modeling placed the novel mutation (p.D1407G) in the EGF-like domain 8 and was predicted to affect interactions with SLIT2 binding partners. Conclusions To the authors’ knowledge, this is the first report of a SLIT2 variant in the context of these ocular findings.