With ongoing improvements in the detection of complex genomic and epigenomic variations, long-read sequencing (LRS) technologies could serve as a unified platform for clinical genetic testing, particularly in rare disease settings, where nearly half of patients remain undiagnosed using existing technologies. Here, we report a simplified funnel-down filtration strategy aimed at enhancing the identification of small and large deleterious variants as well as abnormal episignature disease profiles from whole-genome LRS data. This approach detected all pathogenic single nucleotide, structural, and methylation variants in a positive control set (N = 76) including an independent sample set with known methylation profiles (N = 57). When applied to patients who previously had negative short-read testing (N = 51), additional diagnoses were uncovered in 10% of cases, including a methylation profile at the spinal muscular atrophy locus utilized for diagnosing this life-threatening, yet treatable, condition. Our study illustrates the utility of LRS in clinical genetic testing and the discovery of novel disease variation.