Genetic causes identified for three rare diseases

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A computational approach developed by Mount Sinai Icahn School of Medicine researchers helped to identify previously unknown genetic causes of three rare conditions: primary lymphedema, thoracic aortic aneurysm disease, and congenital deafness.

The research, published Thursday in Nature Medicine, enhances the understanding of the functioning of the genes involved in these disorders, which could pave the way for new treatments, according to the study.

Collectively, rare diseases affect one in 20 people, but few patients receive a genetic diagnosis. Fewer than half of the 10,000 recorded rare diseases have a known genetic cause. Genome sequencing of large cohorts of rare-disease patients provides a route toward discovering genetic causes that remain unknown. However, large genetic datasets slow research down and are challenging to work with. People with rare diseases may struggle for years to obtain a genetic diagnosis.

The researchers sought to develop an approach that would improve the analysis of large genetic datasets from rare-disease cohorts. They built a compact database, called the “Rareservoir,” containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project -- one of the largest datasets of phenotyped and whole-genome-sequenced rare-disease patients.

Using the Bayesian genetic association method BeviMed, the researchers inferred associations between genes and each of 269 rare-disease classes assigned by clinicians to participants. They identified 260 associations between genes and rare-disease classes, including 19 previously unknown and 241 known associations. Through an international academic collaboration, the researchers validated the three most plausible new associations by identifying additional cases in other countries, and through experimental and bioinformatic approaches.

Their work yielded three key pieces of evidence. First, loss-of-function variants in the Erythroblast Transformation Specific-family transcription factor encoding gene ERG leads to primary lymphoedema. Secondly, truncating variants in the last exon of the transforming growth factor-β regulator PMEPA1 gene results in Loeys–Dietz syndrome, a disease characterized by aortic root enlargement. Finally, loss-of-function variants in the GPR156 gene give rise to recessive congenital hearing impairment.

The researchers expect that genetic diagnoses will be more attainable for families with previously unexplained primary lymphedema characterized by tissue swelling, thoracic aortic aneurysm disease, and congenital deafness. They wrote that they hope to see their computational framework accelerate the discovery of still-unknown rare-disease etiologies, and plan to apply their methods in novel ways, using other datasets, with the goal of continuing to unravel the genetic causes of rare diseases.

“While rare diseases are individually rare, collectively they are quite common. It is important for our understanding of human biology and for the development of diagnostics and therapeutics that the remaining causes are found,” Mount Sinai associate professor Ernest Turro, senior study author, noted in a statement. “By developing and applying statistical methods and computational approaches to find new causes of rare diseases, we hope to expand knowledge of the underlying causes of these diseases, hasten the time to diagnosis for patients, and pave the way for the development of treatments.”

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