Examining the phenotypes of MGB Biobank participants with the V142I TTR variant using a genotype first approach

Principal Investigator: Nina Gold, MD

Authors: Emma Perez, MGC, CGC, Sarina Madhavan, Marcie Steeves, MS, CGC, Carrie Blout Zawatsky, MS,CGC Jacob Borgida, Elizabeth Karlson, MD, MS, Robert Green, MPH,MD
Lay Abstract

Hereditary transthyretin amyloidosis (ATTRm) is a protein misfolding disease whose progression can be slowed by timely access to novel treatments. The TTR V142I genetic variant is common in populations with African ancestry and has been linked to ATTRm, but its clinical value has been questioned because not all people with the variant have or will develop the disease. Prior studies show that TTR is often misdiagnosed or underdiagnosed; accurate diagnosis will be critical to fully realize the potential of targeted treatment for ATTRm.

To better understand the clinical value of the TTR V142I variant, we reviewed the medical records of 36 MGB Biobank participants who were identified to have the TTR V142I variant to determine if they had a record of symptoms related to ATTRm. Only one participant was removed from the analysis due to prior diagnosis of the disease. A total of 16 individuals (45%) with no previous diagnosis had at least one manifestation of ATTRm. Our data suggest that clinical features of ATTRm are being missed, leading to underdiagnosis of the disease and missed opportunities for early intervention.

Scientific Abstract

Early diagnosis of hereditary transthyretin amyloidosis (ATTRm) is essential for timely access to novel treatments. The TTR V142I variant is found in 3-4% of African Americans (AA) and 1% of Hispanics. The clinical value of returning TTR as a secondary finding has been debated due to incomplete penetrance. Prior studies demonstrate that TTR is often misdiagnosed or underdiagnosed, leading to underutilization of targeted treatment.

13,345 MGB Biobank participant samples underwent exome sequencing (WES), and 36 have the V142I variant (Median age: 43y). Retrospective chart reviews were performed in order to determine if the participant had the following symptoms: heart failure (HF), cardiomyopathy, carpal tunnel syndrome (CTS), spinal stenosis (SS), and peripheral neuropathy (PN).

A total of 16 individuals (45%) presented with at least one feature of ATTRm.

Our data suggest that individuals with molecular diagnoses and clinical features of ATTRm are underdiagnosed. This finding is consistent with prior studies from a smaller biobank, and in concert, these results may prompt other Biobanks to consider returning TTR findings to participants. Ascertainment of individuals with ATTRm may prompt further diagnostic evaluation, and those who are symptomatic may benefit from access to clinically approved medications and ongoing clinical trials.

Clinical Implications
The TTR gene should be included on population genetic screening lists since it can be difficult to diagnose early. Failure to do so may widen existing healthcare disparities in the diagnosis and treatment of genetic disease.

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