Smith–Magenis syndrome is a complex neurobehavioral genetic disorder with a broad phenotypic spectrum. While the etiology of SMS is commonly attributed to one-copy interstitial deletion in the 17p11.2 region (90–95% of cases), variants identified by sequence analysis in RAI1 have also been reported in 5–10% of cases. In this study, we report a 9-year-old male with global cognitive and psychomotor developmental delay, musculoskeletal and cardiovascular abnormalities, and dysmorphic craniofacial features. Joint analysis was performed on the whole-genome sequencing data obtained from the proband, unaffected parents, and unaffected brother. This quad analysis identified the novel de novo RAI1:c.2736delC variant. This is the first report of this variant in the literature. This report highlights the details of genome analysis and the patient’s phenotypic spectrum.