Rare Disease Day Highlights Diagnostic Delays and Access Barriers to Gene Therapy

Every year on 28 February, the world observes International Rare Disease Day. Rare, or "orphan," diseases are traditionally defined by low population prevalence, affecting fewer than 1 in 2,000 individuals in the European Union and fewer than 200,000 people in the United States. While each condition is individually uncommon, together nearly 8,000 such disorders affect millions worldwide. In India, it is estimated that around 70 million Indians live with one of more than 7,000 rare diseases, many of which are genetic in origin.

Diagnostic delay remains a critical challenge. In congenital afibrinogenemia, an extremely rare congenital bleeding disorder, a median diagnostic delay of over eight years was observed in a prospective Indian cohort, with one child losing vision due to delayed recognition and inappropriate therapy. Three of these four children were initially misdiagnosed as hemophilia. A 22-year review from a major Indian genetics center found that of more than 7,000 referrals, about half had a confirmed rare disease, most commonly involving the blood, muscles, nervous system, or metabolism.

Many patients undergo a "diagnostic odyssey," visiting multiple specialists and undergoing numerous tests before finding an answer, if at all. A 19-year-old with recurrent bleeding and abdominal pain from early childhood who had received multiple transfusions was evaluated at more than 20 medical centers before being diagnosed with Glanzmann thrombasthenia, a rare bleeding disorder which would have caused repeated bleeding into his gut. An infant with severe anemia was repeatedly evaluated and treated for presumed nutritional deficiency before molecular testing revealed a rare cobalamin metabolism disorder. This condition, the inborn cblF defect caused by pathogenic variants in LMBRD1, has been reported only exceptionally in the medical literature, with approximately 20 genetically confirmed cases described worldwide to date.

About 80 per cent of all rare diseases are genetic, which means they are caused by changes in a person's DNA. Advances in genetic testing now allow clinicians to look deeper into the genome than ever before, pinpointing the exact cause of disease. Chromosomal microarray analysis can detect tiny deletions or duplications of DNA known as copy number variations that are a frequent cause of rare diseases. Whole exome sequencing (WES) looks at all the protein-coding regions of the genome (about 1–2 per cent of DNA), and has been shown to provide a diagnosis in many previously undiagnosed rare disease cases. In pediatric care, trio-based exome sequencing (testing the child and both parents) is one of the most successful strategies used to achieve diagnoses when a rare disease is suspected.

Gene therapies are usually one-time treatments that break into cells and modify the disease-causing genes. These therapies can absolutely massively impact the lives of patients with terrible conditions. But they can cost a few million dollars for just one patient, and the fragmented way that care is paid for and delivered creates barriers to equitably delivering those therapies to patients who can benefit.

Geographic location creates significant access barriers. A 34-year-old patient from Lafayette, Louisiana, has retinitis pigmentosa, a rare, inherited eye disease. By the time he was in his 20s, he noticed that his vision had narrowed. There are no options for the specialized care he needs in southern Louisiana, where he lives. His retinal specialist in Louisiana told him he couldn't help with clinical trial access, but there were specialists in Texas who could. The first step would involve a complicated hours-long workup. He made the appointment in Texas and had transportation set up only to find out that his insurance wouldn't cover it because he's not a resident of Texas.

For certain neuromuscular diseases, knowing the specific gene involved can determine whether a patient is eligible for gene therapy or clinical trials. For rare diseases like spinal muscular atrophy (SMA), identifying a mutation in the SMN1 gene can determine whether a patient is eligible for gene therapy (such as onasemnogene abeparvovec) or other targeted treatments. In metabolic disorders such as phenylketonuria or maple syrup urine disease, genetic testing helps pinpoint which enzyme is affected, allowing doctors to tailor dietary restrictions and monitor for specific complications.

Cancer predisposition syndromes represent another rare but important group of inherited genetic disorders, in which germline mutations confer a heightened risk of malignancy, often affecting multiple members within the same family. The absence of timely recognition in earlier siblings underscores the devastating consequence of missed diagnosis in rare genetic disorders, where each missed opportunity represents not only a clinical failure, but also a profound human loss.