Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

AbstractIn sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

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MOLECULAR AUTOPSY: EVALUATION OF SUDDEN UNEXPECTED DEATH CASES IN TERMS OF “KCNQ1” GENETIC VARIATION

International Journal of Medical and Biomedical Studies ◽

10.32553/ijmbs.v3i6.317 ◽

2019 ◽

Vol 3 (6) ◽

Author(s):

Kenan Kaya ◽

Mete Korkut Gülmen ◽

Ayşe Serin ◽

Necmi Çekin ◽

Ahmet Hilal

Keyword(s):

Genetic Variation ◽

Genetic Analysis ◽

Cause Of Death ◽

Conduction System ◽

Sudden Unexpected Death ◽

Age Group ◽

Unexpected Death ◽

Molecular Autopsy ◽

Sequence Variations ◽

Death Cases

Background: Deaths occuring without a known disease and/or a known cause, deaths with non-lethal diseases are interpretated as sudden-unexpected-suspected deaths. Autopsy should always required to evaluate the cause of death. Some of the cases can be termed as negative autopsy since the cause of death can not be determined. This is one of the main interests of the future forensics. Molecular autopsies are one of the main practices of to reduce the negative autopsy ratios. Thus, post-mortem KCNQ1 genetic variation tests are done in sudden unexpected death cases. Material and methods: In this study 0 – 50 years old sudden-unexpected deaths autopsy cases were handled. Samples taken from cases were evaluated and “KCNQ1” genetic variation tests were done in our Department. Results: This study included 47 cases of 42 sudden unexpected death cases (0 – 50 age group) and 5 control group. 15 cases were between 40 – 50 age group and number of cases were increasing with age. 29 of cases (% 69) were male. Evaluation of body-mass index of cases were done and normal weighted cases were the most common with 21 cases (% 50). According to death locations; 17 cases had died (% 45,9) at home. Death location records of 5 cases couldn’t be found. Pathological examinations of all cases were done. We had identified fibrosis and fatty change appearances in SA node of 9 cases (% 21,4) and AV node of 13 cases (% 30,9) especially in conduction tissue examinations. As the result of KCNQ1 genetic analysis of cases, we identified sequence variations in 1638th nucleotid of exon 13 and 1986th nucleotid of exon 16. Conclusion: Cases with conduction system pathology and sequence variations of KCNQ1 genetic analysis shows that we are in need of these tests among routine practice to reduce negative autopsy ratios. Key words: KCNQ1, molecular autopsy, sudden unexpected death, conduction system, negative autopsy.

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Post-Mortem Review and Genetic Analysis of Sudden Unexpected Death in Epilepsy (SUDEP) Cases

Yearbook of Neurology and Neurosurgery ◽

10.1016/j.yneu.2011.04.011 ◽

2011 ◽

Vol 2011 ◽

pp. 42-43

Author(s):

M.J. Brodie

Keyword(s):

Genetic Analysis ◽

Sudden Unexpected Death ◽

Post Mortem ◽

Unexpected Death

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Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death

Journal of Human Genetics ◽

10.1038/jhg.2017.79 ◽

2017 ◽

Vol 62 (11) ◽

pp. 989-995 ◽

Cited By ~ 8

Author(s):

Yuki Oshima ◽

Takuma Yamamoto ◽

Taisuke Ishikawa ◽

Hiroyuki Mishima ◽

Aya Matsusue ◽

...

Keyword(s):

Genetic Analysis ◽

Infant Death ◽

Genetic Screening ◽

Sudden Infant Death ◽

Sudden Unexpected Death ◽

Sudden Infant ◽

Unexpected Death

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Genetic Analysis of Hyperpolarisation-Activated Cyclic Nucleotide-Gated Cation (HCN) Channels in Sudden Unexpected Death in Epilepsy (SUDEP) Cases

Heart Lung and Circulation ◽

10.1016/j.hlc.2011.05.539 ◽

2011 ◽

Vol 20 ◽

pp. S219

Author(s):

E. Tu ◽

L. Waterhouse ◽

J. Duflou ◽

R. Bagnall ◽

C. Semsarian

Keyword(s):

Genetic Analysis ◽

Cyclic Nucleotide ◽

Sudden Unexpected Death ◽

Hcn Channels ◽

Unexpected Death

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Telling Christopher’s Story

Visions ◽

10.1093/med/9780190692070.003.0041 ◽

2019 ◽

pp. 284-290

Author(s):

Jeanne Donalty

Keyword(s):

Cause Of Death ◽

Sudden Unexpected Death ◽

Unexpected Death ◽

Loved One ◽

Helping Others

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with uncontrolled seizures. This section details the lives of people who have lost a loved one to SUDEP and found meaning from their tragedies by helping others in similar situations.

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Time-of-day influences on respiratory sequelae following maximal electroshock-induced seizures in mice

Journal of Neurophysiology ◽

10.1152/jn.00039.2017 ◽

2017 ◽

Vol 118 (5) ◽

pp. 2592-2600 ◽

Cited By ~ 9

Author(s):

Benton S. Purnell ◽

Michael A. Hajek ◽

Gordon F. Buchanan

Keyword(s):

Eye Movement ◽

Cause Of Death ◽

Rem Sleep ◽

Refractory Epilepsy ◽

Time Of Day ◽

Sudden Unexpected Death ◽

Maximal Electroshock ◽

Rapid Eye Movement ◽

Unexpected Death ◽

Sleep State

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in refractory epilepsy patients. Although specific mechanisms underlying SUDEP are not well understood, evidence suggests most SUDEP occurs due to seizure-induced respiratory arrest. SUDEP also tends to happen at night. Although this may be due to circumstances in which humans find themselves at night, such as being alone without supervision or sleeping prone, or to independent influences of sleep state, there are a number of reasons why the night (i.e., circadian influences) could be an independent risk factor for SUDEP. We explored this possibility. Adult male WT mice were instrumented for EEG, EMG, and EKG recording and subjected to maximal electroshock (MES) seizures during wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep during the nighttime/dark phase. These data were compared with data collected following seizures induced during the daytime/light phase. Seizures induced during the nighttime were similar in severity and duration to those induced during the daytime; however, seizures induced during the nighttime were associated with a lesser degree of respiratory dysregulation and postictal EEG suppression. Seizures induced during REM sleep during the nighttime were universally fatal, as is seen when seizures are induced during REM during the daytime. Taken together, these data implicate a role for time of day in influencing the physiological consequences of seizures that may contribute to seizure-induced death. NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP frequently occurs during the night, which has been attributed to an effect of sleep. We have shown that sleep state does indeed influence survival following a seizure. That SUDEP occurs during the night could also implicate a circadian influence. In this study we found that time of day independently affects the physiological consequences of seizures.

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PARATHYROIDS AND CERVICAL THYMUS IN SUDDEN UNEXPECTED DEATH IN INFANCY

PEDIATRICS ◽

10.1542/peds.44.2.225 ◽

1969 ◽

Vol 44 (2) ◽

pp. 225-233

Author(s):

H. A. Ellis ◽

B. Knight

Keyword(s):

Cause Of Death ◽

Parathyroid Glands ◽

Sudden Unexpected Death ◽

Unexpected Death ◽

Thymic Tissue

It has recently been claimed that there is a reduction in the number of parathyroid glands and abnormal fusion of parathyroid and thymic tissues in the sudden unexpected death (SUD) syndrome in infancy. In the present study, the parathyroid glands and thymus were dissected under the stereomicroscope at autopsy in 55 infants, including 31 with features of SUD. The identity of the glands was confirmed histologically. Parathyroid glands were identified in comparable numbers and sites in infants dying with the SUD syndrome or from some ascertainable cause. Cervical thymic tissue was commonly found in infants, whatever the cause of death, and fusion of parathyroid and thymic tissues was not confined to the SUD syndrome. The study provides no evidence to support the claim that there is a deficiency of parathyroid glands in the SUD syndrome or that fusion of thymic and parathyroid tissues normally does not occur.

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