Rare diseases have historically been overlooked because they affect relatively few people. While they are identified and addressed differently around the world, there are over 6,000 known rare diseases – characterised by a wide range of disorders and symptoms that vary not only from disease to disease but also between patients with the same disease. Changing or non-specific symptoms often mask underlying rare diseases, leading to misdiagnosis and delayed treatment.
With up to 90% of rare diseases considered serious or life-threatening, and 95% without a treatment option, those affected often endure chronic, progressive, and debilitating conditions – frequently without answers or support for years.
On the last day of February each year, World Rare Disease Day is celebrated globally to raise awareness for the 300+ million people living with conditions that often go unnoticed, as well as for their families and carers.
For researchers like Dr Yasushi Okazaki and his team at the Intractable Disease Research Center at Japan’s Juntendo University, this occasion also recognises their long-term efforts to find answers for patients living with rare diseases through genetics, providing equitable access to diagnosis, treatment, and social care.
“Seventy-two per cent of rare diseases have a genetic origin,” said Dr Okazaki. “Our work focuses on identifying the causative genes of difficult diseases and using this information to develop potential cures.”
Initially a cardiologist, Dr Okazaki’s career shifted during his graduate studies in the early 1990s as the landmark Human Genome Project took flight. “At the time, everyone spoke of it as the next great project for humanity after the moon landing,” he recalled. “Genetics has the power to unlock our understanding of all human diseases, and I wanted to get as close to that as possible.”
Following five years of acclaimed research in mapping the key gene for hamster cardiomyopathy, and a stint at the first gene centre in Yokohama summarising mouse cDNAs, Dr Okazaki was determined to focus on human diseases. At the Saitama Medical University Research Center for Genomic Medicine, he began devoting himself to identifying causative genes for various rare hereditary diseases, including mitochondrial disorders.
“According to birth calculations, the probability of mitochondrial diseases is approximately 1 in 2,000, with estimates ranging from 1 in 1,500 to 1 in 5,000,” he explained. “Given Japan’s current birth rate of around one million annually, this translates to roughly 200 cases per year, resulting in 200 to 300 patients.”
As the most common congenital metabolic condition, the most severe types of mitochondrial disease mainly occur in childhood. Adult onset, often involving mitochondrial DNA abnormalities, can also be triggered by factors such as stress, causing psychiatric symptoms, cardiomyopathy, seizures, kidney and liver dysfunction, and hearing loss.
“Most genetic diseases have one or two causative genes, but mitochondrial diseases are thought to involve around 1,500,” said Dr Okazaki. “Our team developed a sequencing platform using a mitochondrial disease gene panel based on data from over 2,000 cases. We can now screen 367 causative genes in a sample by sequencing both the patient’s nuclear and mitochondrial DNA, 13 of which were first discovered by us.”
Using whole genome sequencing, RNA sequencing, and functional analyses empowered by MGI’s highly accurate and reliable sequencing tools, Dr Okazaki and his team at Juntendo University have profiled causative genes of mitochondrial diseases in batches, increasing the efficiency of genetic diagnosis. At the same time, finer-grained insights have informed more accurate diagnoses and helped reduce stigma.
“People used to think mitochondrial diseases were inherited only from mothers, so whenever there was a diagnosis, mothers felt guilty, and the paternal grandparents would blame the mother for bringing ‘inferior blood’ into the family,” he said. “In-depth genetic analyses showed that 75% of childhood-onset cases involve nuclear gene abnormalities, with both parents contributing abnormal genes.”
“I remember a woman from a patient support group whose child died tragically due to mitochondrial disease telling me, ‘Thanks to genetic diagnosis, I learned that the disease originated from both parents providing abnormal genes. I felt relieved from all the blame I endured when my child was diagnosed.’”
Equipped with the high-throughput DNBSEQ-G400* sequencer, the center has supported genetic testing for mitochondrial diseases and other rare conditions covered by medical insurance in Japan since 2020. Coverage for disease surveillance expenses allows Dr Okazaki and colleagues to cast a wider net in screening suspected cases, improving diagnostic accuracy.
“A major reason for using MGI instruments is their high-quality data and cost-performance ratio,” he said. “Testing close to 400 causative genes per patient is resource-intensive. MGI’s accuracy, speed, and cost-effectiveness give my team confidence in generating timely and precise diagnoses for those affected, alleviating uncertainty and frustration for patients and families.”
Increasing equity for people living with rare diseases is a priority for many advocates. With genome sequencing costs decreasing, including MGI’s breakthrough sub-$100 human genome, broader access to health and social care, diagnosis, and treatment is becoming more achievable.
“As sequencing costs fall and turnaround times shorten, we aim to create a genomic infrastructure using data from more patients with intractable diseases within three years,” Dr Okazaki shared. “From there, we can supplement clinical trials with genomic and big data from electronic medical records, ultimately translating research findings into viable treatments that patients with rare diseases deserve.”
