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Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families.

Yanushi D Wijeyeratne1,2, Michael W Tanck3, Yuka Mizusawa2,4

  • 1Molecular and Clinical Sciences Research Institute, St George's University of London, Cardiovascular Clinical Academic Group, St George's University Hospitals National Health Service (NHS) Foundation Trust, United Kingdom (Y.D.W., V.B., M.M., H.R., M.P., S.S., E.R.B.).

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Summary

A Brugada syndrome genetic risk score (BrS-GRS) helps explain incomplete penetrance in families with SCN5A mutations. Common genetic variations influence Brugada syndrome (BrS) phenotype, especially in SCN5A-negative relatives.

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Brugada syndromegenetics, humanpenetrancephenotyperisk score

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Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Brugada syndrome (BrS) is an inherited cardiac arrhythmia characterized by a specific ECG pattern.
  • Pathogenic variants in the SCN5A gene are found in a subset of BrS families, but incomplete penetrance is common.
  • The E1784K-SCN5A variant is the most frequently identified SCN5A mutation.

Purpose of the Study:

  • To investigate the association between a Brugada syndrome genetic risk score (BrS-GRS) and the SCN5A mutation type on BrS phenotype.
  • To understand the role of common genetic variations in explaining incomplete penetrance and genotype-negative phenotype-positive individuals in BrS families.

Main Methods:

  • Recruitment of 312 subjects from 16 centers with a spontaneous type 1 Brugada ECG pattern or positive/negative drug challenge, all from cohorts harboring SCN5A mutations.
  • Analysis of single nucleotide polymorphisms (SNPs) previously associated with BrS at genome-wide significance (rs11708996, rs10428132, rs9388451).
  • Calculation of an additive linear genetic risk score (BrS-GRS) based on 6 SNP risk alleles.

Main Results:

  • A BrS-GRS of 4 or more risk alleles was associated with a 4.15-fold increased odds of the BrS phenotype in the total population (P=0.0078).
  • In SCN5A-negative relatives (n=54), a BrS-GRS ≥4 risk alleles showed a significantly higher odds ratio of 22.29 (P=0.0146).
  • Among family members positive for the E1784K-SCN5A mutation, having ≥4 risk alleles increased the odds ratio to 5.12 (P=0.0011).

Conclusions:

  • Common genetic variations contribute to the variable expressivity of the BrS phenotype within SCN5A families.
  • The BrS-GRS and SCN5A mutation genotype are associated with the BrS phenotype, with varying strength depending on SCN5A mutation presence and severity.
  • These findings help explain incomplete penetrance and the occurrence of genotype-negative, phenotype-positive individuals in Brugada syndrome.