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When we think about rare diseases, many of us might imagine them as conditions that are extremely unlikely to affect us or our families. But people often underestimate the collective impact of these diseases and, in certain areas or communities around the world, some diseases that are considered rare globally are actually much more prevalent. With most rare diseases being genetic in nature, caused by mutations in one or more genes, the risk of these conditions is not evenly distributed worldwide, and instead varies between populations depending on social, historical, and environmental factors that shape a population’s genetic makeup. In this article, we explore some of the areas in the world where rare disease prevalence is higher, why this happens, and how we can learn from the genetic makeup of these populations to benefit drug development for more common diseases. When rare diseases are not so rare: Why does this happen? Cousin marriages: A risk factor for rare genetic disorders in certain populations Perhaps the primary driver of rare diseases being more common within specific communities is first- and second-cousin marriages, also known as consanguineous marriages, which have been a longstanding practice in human history and are still a tradition in a number of communities around the world today. A high rate of consanguineous marriages, however, is directly proportional to an elevated risk of recessive genetic disorders, including congenital heart diseases, renal diseases, and rare blood disorders, due to the increased chance of children inheriting two defective copies of the same gene from their parents. Arab nations are a good example of where this practice is common, with rates ranging from 20 to 50% of all marriages, and with first-cousin marriages being particularly common, averaging around 20 to 30%. The preference for marrying relatives in Arab communities is largely driven by socio-cultural reasons, including preserving family structure and assets, facilitating marriage arrangements, fostering harmonious relations with in-laws, and economic benefits related to dowries. Although a decline in consanguineous marriages has been observed in some Arab populations like Jordan, Lebanon, Bahrain, and Palestine, they are still favored in many others, with Saudi Arabia, for example, ranking among the countries with the highest incidence of consanguineous marriages globally. Studies have revealed that consanguineous populations in Saudi Arabia have a high incidence of inborn errors of metabolism, and research has also indicated a correlation between consanguinity and the incidence of rare Mendelian diseases (a group of genetic conditions caused by a mutation in a single gene) in Saudi families, including intellectual impairments, skeletal dysplasia, and neurodevelopmental problems, highlighting the intricate relationship in Saudi Arabia between consanguineous marriages and the inheritance of significant single genetic and chromosomal abnormalities. When cousin marriage fuels rare diseases: Thalassemia and Spoan syndrome To provide a more specific example, Saudi Arabia has one of the highest prevalences of thalassemia, an inherited blood disorder, in the world, ranging from 0.4% in the Northern region to 5.9% in the Eastern region. The United Arab Emirates (UAE), with around a 50% consanguineous marriage rate, also suffers from higher rates of thalassemia, which is noted as a major public health concern since there will be a 25% chance of having a child with thalassemia if a carrier-carrier marriage occurs, leading to a potential increase in the thalassemia population. Another interesting example of where a very specific rare disease has been prevalent among a consanguineous community is a small, remote town – home to fewer than 5,000 people – called Serrinha dos Pintos in the north-eastern region of Brazil. More than 20 years ago, the town was left perplexed due to so many local children losing the ability to walk. A detailed genetic study by the geneticist Silvana Santos and her team eventually followed; they were able to identify a previously unknown condition called Spoan syndrome, which is caused by a genetic mutation and affects the nervous system, gradually weakening the body. It only appears when the altered gene is inherited from both parents. Serrinha has a high rate of consanguineous marriages, with a 2010 study led by Santos showing that more than 30% of couples living there were related. Unfortunately, this figure also meant that a third of these couples were found to have at least one child with a disability. More than 70 cases of Spoan syndrome have now been recorded, with two in Egypt and the rest in Brazil. How founder effect and genetic drift shape rare disease risks in populations According to Neil Ward, vice president and general manager EMEA at PacBio, another driver of rare disease is what is known as the “founder effect,” where a small, isolated population amplifies variants that were rare globally: “Iceland is a classic example, where a few original settlers carried mutations that became common in later generations. Similar effects have been seen in island populations such as Orkney in Scotland, where BRCA mutations associated with breast cancer occur at higher rates.” The impact of paternal age and genetic diseases Ward also commented that, in the Western world, where people are generally having children later in life, research shows that paternal age is strongly linked to an increase in new mutations passed on through sperm. By contrast, he added, conception tends to happen at much younger ages in parts of Africa, leading to very different dynamics, while immigration patterns also change the mix of genetic risk factors across communities over time. The increased burden of rare diseases: What is the direct impact on these communities? For the communities heavily affected by rare diseases, the impact is likely to be profound, particularly when there is no effective treatment or cure for their specific condition. Ward noted that the burden is especially heavy in low- and middle-income countries, where healthcare systems often lack the infrastructure to manage chronic conditions. He provided the example of sickle cell disease, which is much more common among people of African descent and stems from a long evolutionary interplay with malaria. “Genetic changes that altered the shape of red blood cells offered protection against malaria, but when inherited from both parents, those same changes can cause sickle cell disease, which is incurable. To try and control the condition, Nigeria has implemented a premarital sickle cell screening program, with some states making it mandatory in high-risk groups.” Another challenge is that most genetic research has historically focused on people of European descent, meaning that there is a far better understanding of their genetic risk factors, while the causes of disease in other populations remain underexplored. Ward stressed that addressing this disparity requires more inclusive studies, such as the recently published Arab Pangenome that his company PacBio supported. To try to avoid further suffering from rare diseases, some countries have introduced genetic screening programs. In the UAE, for example, Abu Dhabi’s Department of Health recently established a new policy that requires engaged couples to get genetic testing done, along with clinical laboratory blood testing, before they get married. Meanwhile, in Saudi Arabia, there has been a boom in population genetics research over the past decade, of which Fowzan Alkuraya, a young Saudi geneticist, and his colleagues at King Faisal Specialist Hospital and Research Centre (KFSHRC) are now a major part of. They are harnessing cheap, next-generation DNA sequencing to pin down mutations underlying unexplained diseases, and hope that the growing catalog of disease mutations they have found will not only help individual families with inherited diseases have healthy babies, but also lead to premarriage DNA tests for young people that could bring down the high rate of those diseases in Saudi Arabia. Even some countries in Europe have been making moves to prevent rare genetic diseases from proliferating within certain immigrant communities due to consanguineous marriages; Norway passed a ban on cousin marriages last year, while Sweden and Denmark have also announced plans to ban the practice. The hope is that this can prevent the health issues associated with these marriages. On a brighter note: How we can learn from rare disease genetics to benefit larger patient populations There is, fortunately, one small glimmer of hope in all of this, which is that rare disease genetics can sometimes reveal insights that lead to treatments for much larger patient populations. One example of this comes from a small number of people of Afrikaner descent in South Africa who avoided marrying outside of their ethnicity. Some of the children within this community inherited defective copies of the SOST gene, which produces a protein called sclerostin, from both parents and developed extremely dense bones – a condition that, tragically, was life-threatening because of the pressure it placed on the skull. “While there is no gene therapy for this rare disease itself, the biology uncovered proved valuable as it showed that blocking sclerostin increases bone density,” explained Ward. “This opened the door to developing Amgen’s drug, Evenity, for osteoporosis, where the bones lose their density, which now generates more than $1.5 billion per year. It’s a good example of a mainstream medical benefit that originated from studying a rare condition.” Another example, meanwhile, comes from Iceland, where individuals with loss-of-function mutations in the PCSK9 gene were found to have protection against cardiovascular disease despite high-fat diets. This discovery led to Amgen’s Repatha and, with it, a new class of cholesterol-lowering drugs, known as PCSK9 inhibitors, which are now prescribed worldwide. “Both cases underline why pharmaceutical companies and healthcare authorities invest heavily in population-scale genetics: rare disease cases act as 'natural experiments’ that validate drug targets,” expressed Ward. The importance of genetic screening in understanding rare disease populations It is no secret that developing treatments for rare diseases is extremely difficult. However, ensuring that these conditions are scrupulously studied can deliver insights that benefit not just wider populations but also the affected patient communities themselves. “To really understand the biology of rare conditions, you need advanced long-read sequencing, because the genetic causes of these conditions typically stem from complex structural changes that traditional sequencing methods miss,” said Ward. “By uncovering rare disease mechanisms, researchers can identify new drug targets and, in some cases, develop therapies that address the same pathway in a more common disease. “This is why population sequencing initiatives like biobanks are so important. These projects search for individuals who are largely healthy but show unusual characteristics, such as unusually low fat levels, atypical height, or distinctive metabolic traits. These cases can reveal new disease-gene associations.” He added that national screening programs also play a critical role by identifying at-risk populations early, making it possible to connect rare disease genetics with real-world healthcare planning. Furthermore, an important area of research to aid our understanding of disease distribution has been comprehending how many new mutations occur in each generation, with every child inheriting around three billion base pairs of DNA from each parent. Ward explained: “Historically, DNA sequencing technology has allowed us to identify that roughly 60 mutations occur in every child born that were not present in either parent. But that number is much higher than scientists thought. Long-read sequencing has allowed us to see not only single-letter changes but also larger, more complex structural variants such as insertions, deletions, and repeat expansions that were previously missed. With access to more complex areas of the genome, it turns out the actual number is more like 150 new mutations per child, which PacBio technology has been crucial to uncovering.” Studies have also shown that many new mutations originate in sperm and their frequency increases steadily with the father’s age. Certain genomic regions, such as the Y chromosome, show mutation rates up to 30 times higher than the rest of the genome. “This evidence contradicts a long history of social commentary that placed disproportionate blame on maternal health and age for birth defects. Instead, the picture is more complex, with paternal age playing a major role,” added Ward. When asked whether the phenomenon of rare diseases being more common in specific communities should alter how we define whether a disease is rare or not, or whether it is still logical to define a disease as rare based on its global prevalence, Ward answered: “Even when a disease is more common in a particular community, it is usually still rare in overall terms. There isn’t a single global standard for what counts as a rare disease – different regions use different thresholds…That lack of alignment suggests there may be value in developing a global consensus, but we also have to recognise the limitations of drawing hard boundaries.” Indeed, in the European Union (EU), a rare disease is defined as one that affects fewer than five in 10,000, while in the U.S., it is defined as affecting fewer than 200,000 people across the country. “Disease risk is better understood as a spectrum. Setting thresholds can create unintended consequences, such as stigma or loss of research funding if a condition falls just outside the definition,” stressed Ward. “This is especially problematic for patients who may be left behind if their condition is no longer categorised as rare. In medicine more broadly, we often think in black-and-white terms: ill or well, rare or common. But the reality is more nuanced. Conditions like mental health disorders illustrate that variation exists along a gradient, and genetics is no different.”