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1.1. Background: Spine pain is widespread due to degenerative disc disease and facet arthropathy. Most patients improve with supportive conservative care measures, including non-steroidal anti-inflammatories, physical therapy, short episodes of rest, and activity modification. Medical and interventional pain manage ment is reserved for those patients who do not improve within 4 to 6 weeks of standard spine care managed within the primary care setting, after which patients are typically referred to a specialist. Genetic conditions are rarely considered early in the differential diagnosis and may be easily missed in non-responsive patients. 1.2. Methods: We briefly de-scribe two illustrative cases of pa tients with a history of chronic musculoskeletal and spinal pain, whose delayed diagnosis led to improper utilization of medical resources until they were diagnosed correctly and targeted person alized care for their painful syndromes could be instituted. 1.3. Results: After a long history of physiotherapy for sever al years to alleviate muscular and spine pain, a patient with lack of proper control of the trunk and leg muscles causing difficul ties with getting up from a sitting position, walking, and climbing stairs was diagnosed with a new mutation in the KLHL40 gene associated with the pain syndrome of Nemaline Myopathy. A sec ond case a severe scoliosis with short femur leading to dwarfism through sonography investigations was diagnosed via mutation in exon 5 of the FGFR3 gene by WES and Sanger sequencing tests. An aborted fetus whose parents did not carry the mutant allele as sociated with Autosomal dominant thanatophoric dysplasia type I due to a de novo mutation of the FGFR3 gene associated with increased sensitivity of nociceptors such as TNF-α. 1.4. Conclusions: Genetic factors may play a more significant role in unrelenting musculoskeletal and spinal pain syndromes in indi viduals unresponsive to standard conservative care measures than previously thought. Genetic screening, counseling, and a combi nation of targeted interventions aimed at alleviating the harmful effect of the underlying gene defect and the disability associated with painful conditions of the musculoskeletal system affecting lo- http://www.acmcasereport.com/ 2 Volume 10 Issue 19 -2023 Case Report comotion and spinal deformity and balance should be considered early on mainly if the index of suspicion for an underlying genetic condition is high.