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Mayo Clinic Researchers Use Targeted Sequencing to Diagnose Short Telomere Syndrome

NEW YORK (GenomeWeb) – A team from the Mayo Clinic has examined the genetic and phenotypic features that occurs in individuals diagnosed with short telomere syndrome (STS), a condition resulting in symptoms that range from accelerated aging or bone marrow failure to immune and multiple organ problems.

"With the help of this patient series, we demonstrate the potential of using a targeted genomics approach through a unique clinic to identify novel genetic abnormalities associated with short telomeres, and follow such patients prospectively," co-corresponding authors Mrinal Patnaik and Mark Wylam, researchers in the Mayo Clinic's hematology division and pulmonary and critical care medicine division, respectively, wrote with their colleagues.

In this month's issue of Mayo Clinic Proceedings, the researchers shared insights gained from retrospectively analyzing data from 17 patients diagnosed with STS by flow fluorescence in situ hybridization-based telomere length measurements and targeted next-generation sequencing on eight STS-related genes. They also turned to exome sequencing to search for suspicious germline alterations in individuals with short telomeres who did not carry STS variants detected with this panel sequencing approach.

"Our standard approach, in the context of a relevant phenotype, includes a thorough history and physical examination, followed by [telomere length] measurement and NGS," the authors wrote. "If the aforementioned testing result is negative, we proceed to perform a research-based whole-exome sequencing after discussion in a multi-disciplinary tumor board comprising clinicians, bioinformaticians, and molecular biologists."

Patnaik and co-author Abhishek Mangaonkar, who is also with the Mayo Clinic's hematology division, provided additional details on this diagnostic strategy and its potential consequences for STS patient treatment in a review article that considered clinical and genetic features of these conditions. The review first appeared online in Mayo Clinic Proceedings in May, and is included in the July issue of the journal.

Using this strategy, the team tracked down variants in telomere complex genes in the germlines of half a dozen STS patients, or 35 percent of those tested — a set that included two known pathogenic variants in the TERT gene and one pathogenic variant apiece in TERC and DKC1. The two remaining variants in the telomere complex genes TERT and RTEL1 were classified as variants of uncertain significance.

And while most of the patients had telomeres that were far shorter than usual, three STS cases were diagnosed based on the presence of DKC1 or TERG variants in combination with STS-related clinical phenotypes.

Despite their success detecting some germline contributors to STS, Patnaik, Wylam, and their co-authors noted that "only a small number of genes have been identified in human beings, signifying the need for a precision genomics-based approach to identify novel genetic and epigenetic mechanisms of [telomere length] regulation."

When they examined clinical features in the 17 STS cases diagnosed at the Mayo Clinic, meanwhile, the researchers found that 12 of the patients, or 71 percent, experienced idiopathic interstitial pneumonia, while five suffered from unexplained cytopenia and two had cirrhosis of the liver.

Based on these and other results, they concluded that "patients with STS present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit."

The team also examined outcomes over a median of four years in the patients, who received treatments ranging from stem cell to lung transplants. That analysis suggested that the average overall survival time could exceed 15 years, though the authors noted that this endpoint was not reached. 

In a related editorial in the Mayo Clinic Proceedings, Johns Hopkins University oncology researcher Mary Armanios noted that the retrospective cases included in the new study highlight the "opportunities and challenges of integrating molecular testing and of identifying patients who have such heterogeneous clinical presentations of the same molecular pathology."

She explained that it is critical to recognize patients with short telomere-related disease in order to establish a successful treatment regimen, "beyond understanding the basis of genetic susceptibility," adding that "[a]ffected patients are prone to increased toxicities from otherwise routine therapies, especially immunosuppression."