Understanding How Cancer Research Led to the Study of Rare Mendelian Disorders Within the Iranian Population

Understanding How Cancer Research Led to the Study of Rare Mendelian Disorders Within the Iranian Population

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Dr. Mohammad R. Akbari, MD, PhD
Assistant Professor, Institute of Medical Science
Assistant Professor, Dalla Lana School of Public Health

By: Maryam Bagherzadeh

The human genome contains over 20,000 genes that serve as a blueprint for all the proteins that make us into who we are. A single mutation in any of these genes can result in disease. Rare diseases caused by a highly penetrant mutation in a single gene are referred to as “Mendelian disorders”. They are rare in the general population, but some of them are over-represented in other populations. For example, some rare Mendelian disorders inherited recessively are concentrated in certain populations within the MiddleEast. It was actually these disorders that caught the attention of Dr. Mohammad Reza Akbari, a molecular geneticist working at Women’s College Research Institute at Women’s College Hospital.

“As a person that has been born and raised in Iran, I have seen how some of these recessive Mendelian disorders impact peoples’ lives as well as the lives of their loved ones. For this reason, I have always been greatly interested in conducting research in this field, specifically studying recessive Mendelian disorders in this population,” explains Dr. Akbari.

Dr. Akbari and his collaborators have developed a targeted gene-sequencing panel for 26 Mendelian disorders in Iran, which includes over 650 genes. They use this panel to examine the genetic basis of patients with phenotypes that can be categorized into any of the 26 Mendelian disorders. So far, they have tested over 300 patients with a success rate of over 70% for finding the causal genetic mutation for the patients.

Dr. Akbari is an assistant professor at the Dalla Lana School of Public Health in the division of Epidemiology, and an associate member of the IMS at the University of Toronto. His main research focus is on cancer genetics, and he only began studying rare Mendelian disorders in 2010 because of a project on the etiology of esophageal cancer. Dr. Akbari and his colleagues found that mutations in a group of genes, named Fanconi Anemia genes, are associated with an increased risk of being diagnosed with esophageal cancer. Fanconi Anemia is a rare mendelian disorder, which annually impacts three out of every one million live births.

“The groups of patients that we were studying were from the North-East of Iran, a population named Turkmen. This population has one of the highest incidence rates for esophageal cancer worldwide, and as a result, we hypothesized that there may be a genetic basis for this disease,” Dr. Akbari explained. “But our literature search for more information on the Fanconi Anemia genes mutated within Iranian population was very inconclusive. Therefore, we decided that in order to gain more information on the role of Fanconi Anemia genes in relation to esophageal cancer, we first needed to do a thorough study on the genes that are involved in the Fanconi Anemia phenotype in the Iranian population.”

Inspired by this project, Dr. Akbari began to research other rare Mendelian disorders within the Iranian population via a collaboration with Dr. Hossein Najmabadi at University of Social Welfare and Rehabilitation in Tehran. These conditions are rare worldwide, but more common in the Middle Eastern populations, potentially due to the prevalence of consanguineous marriages (the marriage between family relatives, such as first cousins). Some examples include muscular dystrophy, retinitis pigmentosa (which results in hereditary blindness), albinism, and Bardet-Biedl syndrome (a genetic disorder that has an impact on multiple body systems, such as hypogonadism and renal failure).

Dr. Akbari is also studying families with currently unknown genetic disorders. For example, he and his collaborators recently conducted a linkage study on a family with a mysterious auto-inflammatory skin disorder. A linkage study is a method used for genetic mapping, which examines the tendency for genes or genetic markers to be inherited together due to their close location on a chromosome. Although this disorder has not been previously defined, it has a dominant mode of inheritance in this specific family. Dr. Akbari and his collaborators were able to come up with several regions in the genome that could account for this disease. They also conducted next generation sequencing on those regions, leading them to find that the gene called NCSTN was mutated, and accounted for the auto-inflammatory skin phenotype in the family.

While studying rare Mendelian disorders in Iran, Dr. Akbari and his colleagues conducted whole-exome sequencing, hoping to investigate the genetic basis of these diseases. One of the first steps after sequencing the genome is to filter out the genetic variants that are commonly seen in the general population, and therefore very unlikely to be the causative variants for disease. However, the human genome databases that were available at the time were mostly specific to Caucasian, African and East Asian populations. Although the recent 1,000 Genome Project has over 26 different populations in its database, it does not include Middle Eastern populations.

Dr. Akbari explained how this was very problematic for their research on the Iranian population. “At that time, my collaborators and I concluded that if we wanted to continue our work in identifying genes for some of the new phenotypes that we were seeing in Iran, we had to develop our own human genome variations database specific to the population of Iran. Based on that, we came up with a human genome database, which I named Iranome. For this project, we conducted whole-exome sequencing on 800 individuals representing eight different ethnic groups that live in Iran, including Persians, Turks, Lors, Turkmen, Baluches, Kurds, Arabs, and a population who live in the Persian Gulf Islands.”

Importantly, although this project was conducted specifically for Iran’s population, the populations listed are representative of about half a billion people who live in the Middle East. For example, Turkmens who live in the North East of Iran are genetically similar to the Torkmenstan’s population, and the Turks who reside in the North West of Iran share a common genetic basis with people from Azerbaijan and Turkey. Therefore, clinicians, scientists and the general population from the Middle East can take advantage of Iranome by using ethnicity-specific variants found in this database during genetic analysis.

To find out more about Iranome, visit: http://www.iranome.com/.