International Triadin Knockout Syndrome Registry

Clemens, Daniel J.; Tester, David J.; Giudicessi, John R.; Bos, J. Martijn; Rohatgi, Ram K.; Abrams, Dominic J.; Balaji, Seshadri; Crotti, Lia; Fauré, Julien; Napolitano, Carlo; Priori, Silvia G.; Probst, Vincent; Rooryck, Caroline; Roux-Buisson, Nathalie; Sacher, Frédéric; Schwartz, Peter J.; Silka, Michael J.; Walsh, Mark A.; Ackerman, Michael J.

doi:10.1161/circgen.118.002419

Cited by 40 publications

(59 citation statements)

References 41 publications

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“…As noted in the ITKOSR, all symptomatic patients presented between the ages of 1-10 years. 10 In addition to SIDS being a highly heterogeneous disorder caused by a variety of different issues, the observation that patients with TKOS do not seem to present until after their first birthday may provide an explanation for why we did not observe any triadin null cases in our SIDS cohort. We also assessed the distribution of ages within our SUDY cohort and found that only 32 cases, or about 12%, fell between the ages of 1 and 10, likely limiting our ability to capture any triadin knockout cases in this cohort.…”

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 72%

“…It should be noted that these estimates are for triadin null individuals, and not necessarily for TKOS. While TKOS is currently thought to be extremely penetrant (95%) 10 , it remains to be seen whether mild cases will emerge as has been observed for most other arrhythmia syndromes. 16 One of the main issues we encountered by using gnomAD for our prevalence estimates was the poor and variable sequencing coverage of TRDN which suggests that this is a difficult gene to sequence successfully.…”

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 98%

“…14,15 Loss of triadin due to homozygous or compound heterozygous null mutations causes a distinct overlap arrhythmia disorder known as triadin knockout syndrome (TKOS). 6,10 Patients with TKOS typically exhibit clinical features of multiple arrhythmia syndromes including QT prolongation, ventricular ectopy upon stress testing, and T-wave inversion in the precordial leads.…”

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 99%

“…Additionally, 2/21 known TKOS patients have died following sudden cardiac arrest. 10 Therefore, in this study we sought to determine the prevalence of TKOS in a large, multi-center cohort of sudden unexplained death cases. Interestingly, we were not able to identify any triadin null individuals in our 599 SIDS or 258 SUDY cases.…”

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 99%

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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: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 72%

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 98%

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 99%

Section: Estimated Prevalence and Ethnic Distribution Of Tkosmentioning

confidence: 99%

See 2 more Smart Citations

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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“…DHEAS may feasibly influence atrial fibrillation through conversion to biologically active androgens and oestrogens, via vascular remodelling, or through its anti-inflammatory action 40. It is also of interest that microarray analysis has implicated reduced triadin expression in STS-deficient mouse tissues43 as, in man, the absence of cardiac triadin is associated with increased risk of arrhythmia 44 45. Although prescription rates for medication used to treat heart arrhythmias did not differ across groups, this might be explained by the fact that these medications are used to treat other conditions.…”

Section: Discussionmentioning

confidence: 99%

Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank

et al. 2020

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BackgroundX-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning STS. Some medical comorbidities have been identified in XLI cases, but small samples of relatively young patients has limited this. STS is highly expressed in subcortical brain structures, and males with XLI and female deletion carriers appear at increased risk of developmental/mood disorders and associated traits; the neurocognitive basis of these findings has not been examined.MethodsUsing the UK Biobank resource, comprising participants aged 40–69 years recruited from the general UK population, we compared multiple medical/neurobehavioural phenotypes in males (n=86) and females (n=312) carrying genetic deletions spanning STS (0.8–2.5 Mb) (cases) to male (n=190 577) and female (n=227 862) non-carrier controls.ResultsWe identified an elevated rate of atrial fibrillation/flutter in male deletion carriers (10.5% vs 2.7% in male controls, Benjamini-Hochberg corrected p=0.009), and increased rates of mental distress (p=0.003), irritability (p<0.001) and depressive-anxiety traits (p<0.05) in male deletion carriers relative to male controls completing the Mental Health Questionnaire. While academic attainment was unaffected, male and female deletion carriers exhibited impaired performance on the Fluid Intelligence Test (Cohen’s d≤0.05, corrected p<0.1). Neuroanatomical analysis in female deletion carriers indicated reduced right putamen and left nucleus accumbens volumes (Cohen’s d≤0.26, corrected p<0.1).ConclusionAdult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems; altered basal ganglia structure may underlie altered function and XLI-associated psychiatric/behavioural phenotypes. These results provide information for genetic counselling of deletion-carrying individuals and reinforce the need for multidisciplinary medical care.

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Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome

Rabbani

Khorgami

Dalili

et al. 2021

American J of Med Genetics Pt A

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TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice‐site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN‐related patients, including 27 patients from 21 families. The average age‐onset was 30 months (range 1–10) for all cases. Adrenergic‐mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss‐of‐function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic‐mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations.

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International Triadin Knockout Syndrome Registry

Cited by 40 publications

References 41 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

Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank

Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome

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