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Updated: Aug 28, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

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Clinical Risk Score to Predict Pathogenic Genotypes in Patients With Dilated Cardiomyopathy

Luis Escobar-Lopez1, Juan Pablo Ochoa2, Ana Royuela3

  • 1Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, Madrid, Spain; CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN-GUARDHEART), Madrid, Spain.

Journal of the American College of Cardiology
|September 15, 2022
PubMed

Insights

A new Madrid Genotype Score accurately predicts positive genetic test results in patients with dilated cardiomyopathy (DCM) or left ventricular systolic dysfunction (LVSD). This tool aids in identifying individuals likely to benefit from genetic testing, improving clinical decision-making.

Area of Science:

  • Cardiology
  • Genetics
  • Medical Diagnostics

Background:

  • Genetic testing in nonischemic dilated cardiomyopathy (DCM) and isolated left ventricular systolic dysfunction (LVSD) aids family screening and risk stratification.
  • However, a significant proportion of patients have negative genetic test results, limiting its clinical utility.
  • A predictive tool is needed to optimize the selection of patients for genetic testing.

Purpose of the Study:

  • To develop and externally validate a clinical score predicting the likelihood of a positive genetic test result (G+) in patients with DCM/LVSD.
  • To identify key clinical, electrocardiographic, and echocardiographic variables associated with positive genetic findings.

Main Methods:

  • A multivariable logistic regression model was used to identify independent predictors of G+ in 1,015 genotyped DCM/LVSD patients from Spain.
  • The Madrid Genotype Score was created by summing the identified predictors.
  • External validation was performed using data from 1,097 genotyped patients in the Maastricht and Trieste registries.

Main Results:

  • A positive genetic test result (G+) was observed in 37% of the derivation cohort and 26% of the validation cohort.
  • Independent predictors of G+ included family history of DCM, low peripheral ECG voltage, skeletal myopathy, absence of hypertension, and absence of left bundle branch block.
  • The Madrid Genotype Score demonstrated good predictive accuracy, with a C-statistic of 0.74 in both internal and external validation cohorts.

Conclusions:

  • The Madrid Genotype Score is a validated and accurate tool for predicting positive genetic test results in DCM/LVSD patients.
  • This score can assist clinicians in identifying patients most likely to have a positive genetic test, thereby improving the efficiency and adoption of genetic testing.
Abstract

Keywords:
dilated cardiomyopathygenetic variantgeneticsgenotypepredictor

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