A unique triadin exon deletion causing a null phenotype

O’Callaghan, Barry; Hancox, Jules C.; Stuart, Graham; Armstrong, Catherine; Williams, Maggie; Hills, Alison; Pearce, H; Dent, Carolyn L.; Gable, Mary; Walsh, Mark A.

doi:10.1016/j.hrcr.2018.07.014

Cited by 12 publications

(9 citation statements)

References 14 publications

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“…[2][3][4] Since 2012, mutations in TRDN-encoded cardiac triadin have been implicated as an underlying cause in each of these arrhythmia syndromes. [5][6][7][8][9] Interestingly, these patients display clinical features of multiple arrhythmia syndromes including transient QT prolongation, ventricular ectopy upon stress testing, and extensive T-wave inversion in precordial leads V1-V4. This suggests that these patients do not have typical LQTS or CPVT, but instead suffer from a distinct overlap disorder which is now referred to as triadin knockout syndrome (TKOS Despite its malignant and potentially lethal phenotype, the prevalence of TKOS in cases of sudden unexplained death remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population

Clemens

Gray

Bagnall

et al. 2020

Circ: Genomic and Precision Medicine

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Background: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN-encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome (SIDS) and sudden unexplained death in the young (SUDY) is unknown. Methods: Exome sequencing was performed on 599 SIDS and 258 SUDY cases. Allele frequencies of all TRDN-null variants identified in the cardiac specific isoform of TRDN in the Genome Aggregation Database (gnomAD) were used to determine the estimated prevalence and ethnic distribution of TKOS. Results: No triadin null individuals were identified in 599 SIDS and 258 SUDY exomes. Using gnomAD, we estimate the overall prevalence of TKOS to be ~1:22.7 million individuals. However, TKOS prevalence is 5.5-fold higher in those of African descent (~1:4.1 million). Conclusions: TKOS is an exceedingly rare clinical entity that does not contribute meaningfully to either SIDS or SUDY. However, despite its rarity and absence in large sudden death cohorts, TKOS remains a malignant and potentially lethal disorder which requires further research in order to better care for these patients.

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Section: Introductionmentioning

confidence: 99%

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population

Clemens

Gray

Bagnall

et al. 2020

Circ: Genomic and Precision Medicine

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“…In 2018, the first and only homozygous deletion of TRDN (exon 2) was published ( 17 ). The patient was a 16-month-old infant who presented the most severe arrhythmogenic phenotype described thus far—it was characterized by recovered cardiac arrest, recurrent VF despite beta-blockade and flecainide, T-wave inversion in anterior precordial leads, and prolonged rate-corrected QT of 490 ms.…”

Section: Resultsmentioning

confidence: 99%

Pediatric Malignant Arrhythmias Caused by Rare Homozygous Genetic Variants in TRDN: A Comprehensive Interpretation

et al. 2021

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Aim: To perform a comprehensive phenotype-genotype correlation of all rare variants in Triadin leading to malignant arrhythmias in pediatrics.Methods: Triadin knockout syndrome is a rare entity reported in pediatric population. This syndrome is caused by rare variants in the TRDN gene. Malignant ventricular arrhythmias and sudden cardiac death can be a primary manifestation of disease. Although pharmacological measures are effective, some patients require an implantable defibrillator due to high risk of arrhythmogenic episodes.Main Results: Fourteen rare genetic alterations in TRDN have been reported to date. All of these potentially pathogenic alterations are located in a specific area of TRDN, highlighting this hot spot as an arrhythmogenic gene region.Conclusions: Early recognition and comprehensive interpretation of alterations in Triadin are crucial to adopt preventive measures and avoid malignant arrhythmogenic episodes in pediatric population.

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“…При физиологическом уровне Ca 2+ , кальсеквестрин и рианодиновые рецепторы образуют прочную связь, которая пре-пятствует открытию последних. При избытке ионов в саркоплазматическом ретикулуме, сцепление между макромолекулярным комплексом становится ослабленным, что приводит к открытию рианодиновых рецепторов и внутриклеточному высвобождению кальция [34]. Данные процессы играют ключевую роль в генерации возбуждения, адекватного сокращения и регуляции частоты сердечных сокращений.…”

Section: полиморфизм генов предрасполагающих к кавеолинопатиямunclassified

Genetic polymorphisms associated with the development of arrhythmic type of cardiovascular events

et al. 2022

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The review analyzes the global agenda on mutational status of genes associated with adverse cardiovascular events of arrhythmic type. Whole exome sequencing will identify a risk group for the likelihood of early or delayed cardiovascular events of arrhythmic type, especially among patients receiving anticancer therapy with cardiotoxic drugs. The dedicated up-to-date panel of genetic polymorphisms will provide an opportunity to optimize management of patients, based on not only clinical, paraclinical and anamnestic data.

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A unique triadin exon deletion causing a null phenotype

Cited by 12 publications

References 14 publications

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population

Triadin Knockout Syndrome Is Absent in a Multi-Center Molecular Autopsy Cohort of Sudden Infant Death Syndrome and Sudden Unexplained Death in the Young and Is Extremely Rare in the General Population

Pediatric Malignant Arrhythmias Caused by Rare Homozygous Genetic Variants in TRDN: A Comprehensive Interpretation

Genetic polymorphisms associated with the development of arrhythmic type of cardiovascular events

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