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. 2024 Nov 7;25(22):11976.
doi: 10.3390/ijms252211976.

The Yield of Genetic Testing and Putative Genetic Factors of Disease Heterogeneity in Long QT Syndrome Patients

Anna Bukaeva  1 , Alexandra Ershova  1 , Maria Kharlap  1 , Anna Kiseleva  1 , Vladimir Kutsenko  1 , Evgeniia Sotnikova  1 , Mikhail Divashuk  1   2 , Maria Pokrovskaya  1 , Elizaveta Garbuzova  1 , Anastasia Blokhina  1 , Oksana Kopylova  1 , Evgenia Zotova  1 , Anna Petukhova  1 , Anastasia Zharikova  1   3 , Vasily Ramensky  1   3   4 , Marija Zaicenoka  1   5 , Yuri Vyatkin  1   4 , Alexey Meshkov  1 , Oxana Drapkina  1
Affiliations

The Yield of Genetic Testing and Putative Genetic Factors of Disease Heterogeneity in Long QT Syndrome Patients

Anna Bukaeva et al. Int J Mol Sci. .

Abstract

Genetic overdiagnosis of long QT syndrome (LQTS) becomes a critical concern due to the high clinical significance of DNA diagnosis. Current guidelines for LQTS genetic testing recommend a limited scope and strict referral based on the Schwartz score. Nevertheless, LQTS may be underdiagnosed in patients with borderline phenotypes. We aimed to evaluate the total yield of rare variants in cardiac genes in LQTS patients. The cohort of 82 patients with LQTS referral diagnosis underwent phenotyping, Schwartz score counting, and exome sequencing. We assessed known LQTS genes for diagnostics, as per guidelines, and a broader set of genes for research. Diagnostic testing yield reached 75% in index patients; all causal variants were found in KCNQ1, KCNH2, and SCN5A genes. Research testing of 248 heart-related genes achieved a 50% yield of molecular diagnosis in patients with a low Schwartz score (<3.5). In patients with LQTS-causing variants, each additional rare variant in heart-related genes added 0.94 points to the Schwartz score (p value = 0.04), reflecting the more severe disease in such patients than in those with causal variants but without additional findings. We conclude that the current LQTS genetic diagnosis framework is highly specific but may lack sensitivity for patients with a Schwartz score <3.5. Improving referral criteria for these patients could enhance DNA diagnosis. Also, our results suggest that additional variants in cardiac genes may affect the severity of the disease in the carriers of LQTS-causing variants, which may aid in identifying new modifier genes.

Keywords: Schwartz score; clinical heterogeneity; genetic diagnosis; genetic modifiers; genetic testing; long QT syndrome; whole exome sequencing.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The study workflow.
Figure 2
Figure 2
Distribution of Schwartz score and LQTS-causing variants: (A) in the whole cohort and (B) in index patients.
Figure 3
Figure 3
The yield of causal variants for LQTS: (A) in the whole cohort and (B) in index patients.
Figure 4
Figure 4
Venn diagram showing the distribution of genetic findings among patients.
Figure 5
Figure 5
Distribution of unique genetic variants found in this study by genes.
See this image and copyright information in PMC

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