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News & Articles > Whole genome sequencing improves outcomes of genetic testing in patients with hypertrophic cardiomyopathy

HOT OFF THE PRESS!

 

Originally published as an update to Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 11th Edition

 

Debra L. Beck & Eugene Braunwald, MD

Date Published: November 2, 2018

 

Whole genome sequencing improves outcomes of genetic testing in patients with hypertrophic cardiomyopathy

Sequencing a broader range of genes along with intronic and intergenic regions, with greater sensitivity for structural variation could be expected to “greatly improve the diagnostic rate, but the gains in this domain appear relatively muted,” wrote editorialists led by Dr. E Ashley. The findings of this study are intriguing, particularly the yield from “interrogating deep intronic variants…” and demonstrate the “potential incremental value of genome sequencing” in HCM, but there are several challenges remaining before this technology can be deployed. These include the issue of determining that putative genes are causal for disease, in part because “the case for many genes previously held to be causal appears to diminish when population site frequency spectra are taken into account leading to a shortening rather than lengthening of our causal gene list,” they said.

Summary

The investigators concluded that WGS can detect genetic variants not identified with sequencing of protein-coding exons only, thereby improving the yield of genetic testing for HCM over targeted gene sequencing approaches and offering more accurate diagnosis and management for affected families.

“Genetic testing of patients with familial HCM should include protein coding and noncoding regions of genes that have established associations with the disease as well as genes that cause diseases that mimic HCM and variants predicted to cause RNA spicing errors,” wrote Bagnall et al.

Comments

Sequencing a broader range of genes along with intronic and intergenic regions, with greater sensitivity for structural variation could be expected to “greatly improve the diagnostic rate, but the gains in this domain appear relatively muted,” wrote editorialists led by Dr. E Ashley. The findings of this study are intriguing, particularly the yield from “interrogating deep intronic variants…” and demonstrate the “potential incremental value of genome sequencing” in HCM, but there are several challenges remaining before this technology can be deployed. These include the issue of determining that putative genes are causal for disease, in part because “the case for many genes previously held to be causal appears to diminish when population site frequency spectra are taken into account leading to a shortening rather than lengthening of our causal gene list,” they said.

 

 

Reference
  1. R Zilberszac, G Heinze, T Binder, et al: Long-Term Outcome of Active Surveillance in Severe But Asymptomatic Primary Mitral Regurgitation. JACC Cardiovasc Imaging.11(9): 1213-1221. 2018 Sep. 30031699

 

 

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine features a unique update program by Dr. Braunwald, creating a “living textbook” by featuring weekly Hot off the Press, periodic Late-Breaking Clinical Trials (including links to authors’ presentation slides), and monthly Focused Reviews.

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