Genetic causes of three previously unexplained

Image: Daniel Greene, PhD, and colleagues used a computational approach to identify previously unknown genetic causes of three rare diseases: primary lymphedema, thoracic aortic aneurysm, and congenital deafness. In this microscopic image of cells, a mutated form of a protein called ERG, which is present in some lymphedema patients, is shown in green, while cell nuclei are shown in blue. Normally, the ERG protein only exists within cell nuclei. However, the mutated form observed in patients is distributed outside the cell nucleus in the cytoplasm of the cells. see more

Image credits: Daniela Pirri, PhD, and Graeme Birdsey, PhD, from the National Heart and Lung Institute, Imperial College London, who are both co-authors of the Nature Medicine article.

NEW YORK, NY (March 16, 2023) – Researchers at the Icahn School of Medicine at Mount Sinai and colleagues have identified previously unknown genetic causes for three rare diseases using a new computational approach they developed to analyze large genetic data sets of rare disease cohorts discovered : primary lymphedema (characterized by tissue swelling), thoracic aortic aneurysm and congenital deafness. The work was carried out in collaboration with colleagues from the University of Bristol, UK; KU Leuven, Belgium; the University of Tokyo; the University of Maryland; Imperial College London and others from around the world.

An improved understanding of the functions of the genes involved in these and other diseases could pave the way for the development of treatments. The findings were published in the March 16 online issue of Nature Medicine [DOI: 10.1038/s41591-023-02211-z].

Rare diseases affect about 1 in 20 people, but only a minority of patients receive a genetic diagnosis. Less than half of the 10,000 rare diseases recorded have a known genetic cause. Genome sequencing of large cohorts of rare disease patients offers a route to uncovering the still unknown genetic causes. But working with large genetic datasets is difficult and significantly slows down research, the researchers say.

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“While rare diseases are rare individually, they are quite common overall. Finding the remaining causes is important to our understanding of human biology and to the development of diagnostics and therapeutics,” said lead study author Ernest Turro, PhD, Associate Professor of Genetics and Genomics Sciences at Icahn Mount Sinai. “Many people with a rare disease struggle for years to get a genetic diagnosis. By developing and applying statistical methods and computational approaches to find new causes of rare diseases, we hope to advance knowledge of the underlying causes of these diseases, shorten the time to diagnosis for patients, and pave the way for development of treatments.”

Researchers examined a collection of 269 rare disease classes using data from 77,539 participants in the 100,000 Genomes Project, one of the largest datasets of phenotyped and whole-genome sequenced rare disease patients. Researchers identified 260 associations between genes and rare disease classes, including 19 associations previously missing from the literature. Through an international academic collaboration, the authors validated the three most plausible novel associations by identifying additional cases in other countries and through experimental and bioinformatic approaches.

“We hope that our computational framework will help accelerate discovery of the remaining unknown etiologies of rare diseases across the board. For now, we anticipate that genetic diagnosis will be possible for certain families with previously unexplained primary lymphedema, thoracic aortic aneurysm and deafness,” said Dr. Daniel Greene, postdoctoral fellow at Icahn Mount Sinai and lead author of the study. “We also plan to apply our methods in novel ways and to other datasets, with the aim of further unraveling the genetic causes of rare diseases.”

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The publication is entitled “Genetic Association Analysis of 77,539 Genomes Reveals Rare Causes of Disease”.

For the full list of authors and funding details, see the paper at

The National Organization for Rare Disorders has designated the Department of Medical Genetics and Genomics at Mount Sinai Hospital as a Center of Excellence in Rare Diseases.

About the Icahn School of Medicine at Mount Sinai

The Icahn School of Medicine at Mount Sinai is internationally recognized for its excellence in research, education and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health care systems in the United States, serving a large and diverse patient population.

Icahn Mount Sinai ranks 14th nationwide for funding from the National Institutes of Health (NIH) and ranks in the 99th percentile of research dollars per investigator according to the Association of American Medical Colleges. Icahn Mount Sinai has a talented, productive and successful faculty. More than 3,000 full-time scientists, educators, and clinicians work within and between 34 academic departments and 35 multidisciplinary institutes, a structure that allows for tremendous collaboration and synergy. Our focus on translational research and therapeutics is evident in areas as diverse as genomics/big data, virology, neuroscience, cardiology, geriatrics, and gastrointestinal and liver diseases.

Icahn Mount Sinai offers highly competitive MD, PhD and Masters programs with approximately 1,300 current enrollments. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows being trained throughout the healthcare system. In addition, more than 550 postdocs are in training within the healthcare system.

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A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, works with faculty and trainees to pursue optimal intellectual property commercialization and ensure that Mount Sinai’s discoveries and innovations are translated into healthcare products and services available to the public benefit.

Icahn Mount Sinai’s commitment to pioneering science and clinical care is reinforced with academic affiliations that complement and complement the school’s programs.

Through Mount Sinai Innovation Partners (MSIP), the healthcare system facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. In addition, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk and others.

The Icahn School of Medicine at Mount Sinai is located in New York City on the border of the Upper East Side and East Harlem, and classroom instruction takes place on a campus overlooking Central Park. Icahn Mount Sinai’s location provides many opportunities to interact with and care for diverse communities. Learning extends well beyond the confines of our physical campus to the eight hospitals of the Mount Sinai Health System, our academic partners, and worldwide.

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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Beth Israel; Mount Sinai Brooklyn; Mount Sinai morning side; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.


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article title

Genetic association analysis of 77,539 genomes reveals rare causes of disease

Article publication date

March 16, 2023