Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis

Dewar, Laura; Alcaide, Miguel; Fornika, Daniel; D’Amato, Luisa; Shafaatalab, Sanam; Stevens, Charles M.; Balachandra, Thambirajah; Phillips, Susan M.; Sanatani, Shubhayan; Morin, Ryan D.; Tibbits, Glen F.

doi:10.1161/circgenetics.116.001738

Cited by 28 publications

(22 citation statements)

References 43 publications

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“…A total of 20 original research studies [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and seven case reports [31][32][33][34][35][36][37] thus met the inclusion criteria for the review, which included at least one infant greater than 1-year-old in their study (►Table 1). One of the seven case reports, however, 34 was also represented in one original research article.…”

Section: Resultsmentioning

confidence: 99%

“…the results of a molecular diagnosis have clinical value for relatives who may carry the same mutations; some of which are already clinically actionable. 6,12 This review has collated the results from previous molecular autopsy related studies and showed that a median of 4% of previous SIDS cases can potentially be resolved by a molecular autopsy. While this was significantly lower than the yield from older cohorts of SUDY, these results would have been of particular value to the respective family members.…”

Section: Discussionmentioning

confidence: 99%

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A Systematic Review of Molecular Autopsy Studies in Sudden Infant Death Cases

2018

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Sudden unexpected death is an upsetting event, which can remain unexplained even after post-mortem investigation. Internationally, molecular autopsies have shown to resolve up to 44% of unexplained cases; however, it is currently unclear how many of these were infants. This systematic literature review showed that significantly fewer infant cases were resolved (median: 4%) compared with cohorts of 1 to 45 years old (median: 32%). Further, no study involving indigenous African participants has yet been published. Overall, molecular autopsies hold immense value to living family members and is motivation to explore new avenues in infant cohorts.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Systematic Review of Molecular Autopsy Studies in Sudden Infant Death Cases

2018

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“…The availability of large panels and of exome screening has allowed investigators to discover pathogenic variants in genes initially unexpected to be related to the phenotype. In the case of Pkp2 , variants have been detected in idiopathic ventricular fibrillation and SCD (36, 37), possible catecholaminergic polymorphic ventricular tachycardia (38), HCM, DCM and left ventricular non-compaction (39–41). The association between Pkp2 mutations and idiopathic SCD is not that surprising, considering that often SCD is the earliest manifestation in ACM athletes before the onset of overt cardiomyopathy.…”

Section: Additional Cardiac Phenotypes Linked To Pkp2mentioning

confidence: 99%

Pleiotropic Phenotypes Associated With PKP2 Variants

Novelli

Malkani

Cerrone

2018

Front. Cardiovasc. Med.

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Plakophilin-2 (PKP2) is a component of the desmosome complex and known for its role in cell-cell adhesion. Recently, alterations in the Pkp2 gene have been associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy (ACM or ARVC), Brugada syndrome (BrS), and idiopathic ventricular fibrillation to name the most relevant. However, the assessment of pathogenicity regarding the genetic variations associated with Pkp2 is still a challenging task: the gene has a positive Residual Variation Intolerance Score and the potential deleterious role of several of its variants has been disputed. Limitations in facilitating interpretation and annotations of these variants are seen in the lack of segregation and clinical data in the control population of reference. In this review, we will provide a summary of all the currently available genetic information related to the Pkp2 gene, including different phenotypes, ClinVar annotations and data from large control database. Our goal is to provide a literature review that could help clinicians and geneticists in interpreting the role of Pkp2 variants in the context of heritable sudden death syndromes. Limitations of current algorithms and data repositories will be discussed.

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“…With the power of massively parallel sequencing, testing a large number of cardiac disease‐associated genes simultaneously has become feasible. There are now several reports of postmortem testing to identify pathogenic variants directly linked to an underlying heritable cardiac disease; hence, the potential for fatal arrhythmia and sudden death . When there is insufficient evidence to classify variants as either benign or pathogenic, they are considered variants of uncertain significance (VUS).…”

Section: Introductionmentioning

confidence: 99%

“…There are now several reports of postmortem testing to identify pathogenic variants directly linked to an underlying heritable cardiac disease; hence, the potential for fatal arrhythmia and sudden death. [1][2][3][4][5][6] When there is insufficient evidence to classify variants as either benign or pathogenic, they are considered variants of uncertain significance (VUS). In our previous study in which 89 cardiac genes were analyzed in a large cohort of 296 sudden unexpected deaths (SUD), 2 we identified a large preponderance of VUS in various genes, including the pacemaker gene, HCN4.…”

Section: Introductionmentioning

confidence: 99%

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death

Dong

Subbotina

Williams

et al. 2019

Pacing Clinical Electrophis

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The HCN4 gene encodes a subunit of the hyperpolarization‐activated cyclic nucleotide‐gated channel, type 4 that is essential for the proper generation of pacemaker potentials in the sinoatrial node. The HCN4 gene is often present in targeted genetic testing panels for various cardiac conduction system disorders and there are several reports of HCN4 variants associated with conduction disorders. Here, we report the in vitro functional characterization of four rare variants of uncertain significance (VUS) in HCN4, identified through testing a cohort of 296 sudden unexpected natural deaths. The variants are all missense alterations, leading to single amino acid changes: p.E66Q in the N‐terminus, p.D546N in the C‐linker domain, and both p.S935Y and p.R1044Q in the C‐terminus distal to the CNBD. We also identified a likely benign variant, p. P1063T, which has a high minor allele frequency in the gnomAD, which is utilized here as a negative control. Three of the HCN4 VUS (p.E66Q, p.S935Y, and p.R1044Q) had electrophysiological characteristics similar to the wild‐type channel, suggesting that these variants are benign. In contrast, the p.D546N variant in the C‐linker domain exhibited a larger current density, slower activation, and was unresponsive to cyclic adenosine monophosphate (cAMP) compared to wild‐type. With functional assays, we reclassified three rare HCN4 VUS to likely benign variants, eliminating the necessity for costly and time‐consuming further study. Our studies also provide a new lead to investigate how a VUS located in the C‐linker connecting the pore to the cAMP binding domain may affect the channel open state probability and cAMP response.

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Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis

Cited by 28 publications

References 43 publications

A Systematic Review of Molecular Autopsy Studies in Sudden Infant Death Cases

A Systematic Review of Molecular Autopsy Studies in Sudden Infant Death Cases

Pleiotropic Phenotypes Associated With PKP2 Variants

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death

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