Titin‐truncating variants are associated with heart failure events in patients with left ventricular non‐compaction cardiomyopathy

Li, Shijie; Zhang, Ce; Liu, Nana; Bai, Hui; Hou, Chenping; Song, Lei; Pu, Jielin

doi:10.1002/clc.23172

Cited by 11 publications

(10 citation statements)

References 23 publications

(28 reference statements)

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“…Variants in specific genes were associated with worse outcome in LVNC, as reported for variants in Lamin A/C, RBM20, TAZ, Titin-truncating variants and non-sarcomere genes in general (13,37,39,40). Overall, larger cohorts, and genotype-phenotype studies analyzing the correlation between genetic background and clinical outcome are needed in the future.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 84%

Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy

et al. 2021

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Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear.Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint.Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2–44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis.A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE.Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE.Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.

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Section: Genotype-phenotype Correlationmentioning

confidence: 84%

Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy

et al. 2021

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“…In the past few years, some studies have focused on truncated TTN variants as potential causes of LVNC [43][44][45]. However, to our knowledge, no studies investigating the role of rare missense TTN variants in LVNC have been published to date.…”

Section: Cardiomyopathiesmentioning

confidence: 99%

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Martínez-Barrios

Sarquella-Brugada

Pérez-Serra

et al. 2022

JPM

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The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

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“…TTN truncating variants are both associated with LVNC (Li et al, 2019;Sedaghat-Hamedani et al, 2017) and DCM (Herman et al, 2012). They are the most frequent genetic findings in idiopathic DCM, being present in 15-25% of the cases and are also frequent in peripartum cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes

Delplancq

Tarris

Vitobello

et al. 2020

American J of Med Genetics Pt C

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PRDM16 (positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074–3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non‐compaction (LVNC) with a PRDM16 variant. The third‐trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly. Endocardial fibroelastosis was associated with non‐compaction of the myocardium of the left ventricle. Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16. ES also identified two rare variants of unknown significance, according to the American College of Medical Genetics and Genomics guidelines, in the titin gene (TTN): a de novo missense p.(Lys14773Asn) variant and a c.33043+5A>G variant inherited from the mother. Along with the PRDM16 de novo probably pathogenic variant, TTN VOUS variants could possibly contribute to the severity and early onset of the cardiac phenotype. Because of the genetic heterogeneity of cardiomyopathies, large panels or even ES could be considered as the main approaches for the molecular diagnosis, particularly in fetal presentations, where multiple hits seem to be common.

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Titin‐truncating variants are associated with heart failure events in patients with left ventricular non‐compaction cardiomyopathy

Cited by 11 publications

References 23 publications

Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy

Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes

Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes

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