From Mendel to genetic rare disease diagnosis: Two centuries of innovation.

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Enlightened breakthroughs...

More than 350 million people live with rare disorders, that is, a condition with which fewer than 200,000 have been diagnosed. About 80 percent of these rare disorders are genetic in origin, and 95 percent have no treatment approved by the FDA.

Our ability to better understand, diagnose and potentially find treatments for these conditions was significantly advanced by the Human Genome Project (HGP). From October 1990 until its completion in April 2003, the HGP brought together a team of international researchers who collectively defined over 90% of the human genome [i].

However, it would be fair to argue that the journey to understanding the human genome began with Gregor Johann Mendel, who is now recognised as the father of genetics. Born 200 years ago, in 1822, Mendel put his interest in plant genetics into practice with pea plant experiments conducted between 1856 and 1863, which established many of the rules of heredity, now referred to as the laws of Mendelian inheritance [ii].

His work was published in 1866 but was then forgotten about until 1900, when three researchers, Hugo de Vries, Carl Correns, and Erich Tschermak, independently realised the meaning and importance of Mendel`s groundbreaking work.

Mendel’s theories were finally associated with human disease by Sir Archibald Edward Garrod, who published the first findings from a study on recessive inheritance in human beings in 1902 [iii]. In 1909, the term “gene” was introduced for Mendel’s “traits” [iv].

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From the HGP to innovation in rare diseases

Mendel provided the foundation, but it is the work carried out through the HGP that has helped to truly advance understanding of the causes of rare disorders. It has given scientists and clinicians the ability to identify potential disease-causing mutations across the genome at scale, something that was previously impossible. And, crucially, it has helped to accelerate the search for therapies and preventative approaches.

Yet perhaps one of the toughest challenges for people living with a rare disease and their families is getting the right diagnosis. A recent survey of patients and physicians found that it took an average of 5.6 years in the United Kingdom to obtain a diagnosis for a rare disease. In the United States, the average time to diagnosis came to 7.6 years.

Because of the rarity of many syndromes and their low prevalence, research into many disorders is lacking. This means there is often limited knowledge and understanding about how rare diseases are inherited, caused, or even their symptoms.

This lack of knowledge and understanding increases the risk of misdiagnosis for rare disease. For example, 56% of Ehlers-Danlos patients are misdiagnosed at some point in their diagnostic journey. Some rare disease patients receive up to 8 wrong diagnoses before reaching the right one.

Difficulties with a diagnosis can be frustrating both to people living with disease and healthcare professionals (HCPs), and ultimately can have serious medical and financial implications too. An assessment of the diagnosis of 8 unique rare diseases in Europe found that approximately 40% of patients surveyed initially received an erroneous diagnosis, sometimes resulting in inappropriate medical interventions such as surgery, medication use, or psychiatric intervention.

The medical issues related to delayed diagnosis of rare diseases are numerous. In a fatty acid oxidation disorder, for example, the absence of prompt diagnosis and treatment can lead to a metabolic episode resulting in serious, life‐threatening complications. In another example, although enzyme replacement therapies are available that prevent disease progression in certain lysosomal storage disorders, delays in diagnosis and treatment can lead to the build-up of cellular by-products, which significantly affects morbidity and mortality.

While the cost of doing genetic testing has come down dramatically since the HGP – with sequencing falling from US$ 3 billion in 2001 to US$ 1000 in 2018 – it is not feasible to test every person with unexplained symptoms for every rare disease. What we need, therefore, is a way to enable HCPs to triage more people into the right diagnostic pathway.

The clues are locked-up in the EMR

With the growing use of electronic medical records (EMRs) and the advance of other electronic health data, there is a wealth of health data available to HCPs to help with diagnosing people living with disease. Yet it remains difficult to identify individuals suffering from rare diseases, which, in turn, is an obstacle to achieving many other clinical and research goals.

A patient's medical record can contain more than 50,000 possible data points from which a clinician has to discern the pattern of disease. The problem is similar to trying to distinguish thousands of constellations of stars in the night sky. Clinicians today are looking at the equivalent of more than 10-night skies to pick out individual constellations that represent the rare disease – most of which will be unfamiliar to them.

AI can help HCPs unlock those clues

Machine learning is particularly good at digesting large amounts of data very quickly and identifying patterns or finding anomalies or outliers in that data. As a result, an important application in healthcare is the development and implementation of more accurate clinical prediction models (algorithms, tools, or rules) to help HCPs improve screening, diagnosis, and the prediction of diseases.

When applied well, AI or machine learning techniques can produce accurate, evidenced, earlier prediction of disease risk at the individual patient level, often well before clinicians can. This means that more people living with a rare disease can be diagnosed and receive the treatment or support they need to manage their condition much earlier.

The next breakthroughs

We have come a long way since Mendel’s original work was published in 1866, but there is still a long way to go. Our knowledge of the human genome is not enough on its own but combined with breakthrough innovations in AI phenotyping and coupled with clinical expertise, will enable us to accelerate our understanding of rare diseases and help to change the lives of people living with a rare disease.

[i] National Human Genome Research Institute,

[[ii] Gregor Mendel's principles of inheritance form the cornerstone of modern genetics. So just what are they?

[iii] DNA from the beginning,


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