(Un)Stuck Between a Rock and a Hard Place via Genome Sequencing
by Amanda Chase, PhD
April 6, 2023
“To be rare, or not to be, that is the question”. Rare diseases, despite their name, are by no means a rare phenomenon. On the contrary, they are diseases that are ‘rarely’ correctly diagnosed and ‘rarely’ properly treated. The estimated over 10,000 rare disease means that, collectively, over 30 million individuals are affected by a rare disease. There is a critical need, therefore, to improve diagnosis of rare diseases for better treatment of patients. In their recent publication in The New England Journal of Medicine, senior authors and CVI members Nick Leeper, MD, and Nazish Sayed, MD, PhD, present a case for how whole genome sequencing can be a critical tool for rare disease diagnosis and treatment.
Whole genome sequencing (WGS) is a powerful tool that can be used for personalized medicine. Each of us has a unique DNA pattern, similar to unique fingerprints. That pattern is built from the order of nucleotides, the building blocks of DNA. Learning the order of those nucleotides is called sequencing. Learning the order of someone’s unique genetic code, or genome, is referred to as WGS. Initially used as a research tool, WGS moved into use with patients more recently, and has opened the door for personalized medicine and guiding therapeutic interventions. It can be a useful tool, especially for rare diseases, decreasing the time to diagnosis, detecting more rare diseases than other methods, and providing a greater diagnostic yield. The authors of this publication shared just how powerful WGS can be, and how its early use can have profound implications for the patient.
The team had a patient with diabetes who was experiencing numbness and slight discoloration of his toes and fingers, later developing a non-traumatic wound. Subsequently, the patient developed further progressing symptoms that were not typical, in fact uncharacteristic of considered diagnoses. They were able to determine that the patient had severe arterial calcification, a buildup of calcium in the arteries of muscles such as the thigh. The calcium buildup can also be considered a hardening of the arteries.
It can lead to inadequate blood supply to the legs, for example. The authors turned to WGS when the clinical findings continued to be inconsistent with considered diagnoses, seeking an alternative diagnosis. Using whole genome sequencing, the team found that there was a change in the usual nucleotide pattern (a missense mutation) in a specific gene (NT5E gene). This change led to a decrease in an enzyme CD73 that has a central role in tissue calcification. This led to a diagnosis of arterial calcification due to a deficiency of CD73, ACDC, a rare adult-onset disease. This enabled a treatment plan that included an agent that could reduce the levels of calcium, a calcium chelator.
Whole genome sequencing was instrumental in allowing a diagnosis and subsequent treatment that healed the patient’s wounds, improving his symptoms. This additionally demonstrated that the chelating agents such as sodium sulfate that affect calcium metabolism could be used in progressive calcification disorders. It also suggests that early recognition of the disease, and therefore earlier treatment, could have lessened the impact of the disease, even saving the lost limbs. Overall, this study shows how powerful gene sequencing can be in directing clinicians to an alternate diagnosis, improving patient treatment.
Other authors include Tom Alsaigh, Gurpreet Dhaliwal, and Eri Fukaya. Funding was provided by NIH R01 HL158641, R01 HL161002, and American Heart Association (AHA) SFRN grant 869015 (Sayed N) and R35 HL144475 (Leeper N).