Post-mortem genetic investigation of cardiac disease–associated genes in sudden infant death syndrome (SIDS) cases

Köffer, Jasmin; Scheiper-Welling, Stefanie; Verhoff, Marcel A.; Bajanowski, Thomas; Kauferstein, Silke

doi:10.1007/s00414-020-02394-x

Cited by 11 publications

(9 citation statements)

References 29 publications

(46 reference statements)

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“…In 3.5% of the SIDS cases, a genetic polymorphism in a cardiac myopathy gene was reported (145). Although it is very important to detect and evaluate the genetic variants in order to counsel the family in a SIDS case, but it should be evaluated and labeled carefully as "pathogenic" or "informative" as 4.3% was found to be pathogenic and 13% as informative in the recent study mentioned above (143) which is much lower that assumed previously.…”

Section: Discussionmentioning

confidence: 80%

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome

Mehboob

Kurdi

Ahmad³

et al. 2021

Front. Pediatr.

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Background: Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches.Methods: This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis.Results: After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, “hsa-miR-133a-3p” was found to be prevalent in the targeted genes.Conclusions: Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.

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Section: Discussionmentioning

confidence: 80%

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome

Mehboob

Kurdi

Ahmad³

et al. 2021

Front. Pediatr.

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“…Previous studies have reported genetic diseases in 13% to 75% of infant deaths in various subpopulations with various genetic tests. [15][16][17][18][19][20][21][22][23][24][25][26] However, most of these studies were small, limited to SIDS, and used exome sequencing, and all were retrospective. In the current study, all infant deaths were examined by WGS, and most were prospectively followed since ICU admission.…”

Section: Discussionmentioning

confidence: 99%

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

et al. 2023

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ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, Setting, and ParticipantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main Outcomes and MeasuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and RelevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

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“…The DNA of all cases was analyzed for sequence variations using the TruSight cardio panel (Illumina) consisting of 174 genes with known cardiac associations. Paired-end libraries were prepared following the manufacturer’s protocol Nextera™ Flex for Enrichment as described previously [ 18 , 19 ]. Sequencing was performed on the Illumina® MiniSeq™ system (2 × 150 bp paired end reads).…”

Section: Methodsmentioning

confidence: 99%

Variant interpretation in molecular autopsy: a useful dilemma

et al. 2022

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Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS – potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental.

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Post-mortem genetic investigation of cardiac disease–associated genes in sudden infant death syndrome (SIDS) cases

Cited by 11 publications

References 29 publications

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

Variant interpretation in molecular autopsy: a useful dilemma

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