No genetic basis is currently established that differentiates hypermobility spectrum disorders (HSD) from hypermobile Ehlers–Danlos syndrome (hEDS). Diagnosis is entirely based on clinical parameters with high overlap, leading to frequent misdiagnosis of these two phenotypes. This study presents a landscape of DNA mutations through whole-exome sequencing of patients clinically diagnosed with generalized HSD. In this study, three genes (MUC3A, RHBG, and ZNF717) were mutated in all five patients evaluated. The functional enrichment analysis on all 1162 mutated genes identified the extracellular matrix (ECM) structural constituent as the primary overrepresented molecular function. Ingenuity pathway analysis identified relevant bio-functions, such as the organization of ECM and hereditary connective tissue disorders. A comparison with the matrisome revealed 55 genes and highlighted MUC16 and FREM2. We also contrasted the list of mutated genes with those from a transcriptomic analysis on data from Gene Expression Omnibus, with only 0.5% of the genes at the intersection of both approaches supporting the hypothesis of two different diseases that inevitably share a common genetic background but are not the same. Potential biomarkers for HSD include the five genes presented. We conclude the study by describing five potential biomarkers and by highlighting the importance of genetic/genomic approaches that, combined with clinical data, may result in an accurate diagnosis and better treatment.