Introduction
Methods
Inclusion criteria
Clinical data
Genetic analyses
Interpretation of identified sequence variants
Ethics approval
Results
ID | Age | Sex | Activity | Details of event | Clinical history | Investigation | Family history | Autopsy findings | Genetic findings | Familial cascade screening | Diagnosis |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 28 | F | Unknown | Found deceased at home Not witnessed | Syncope 2 days before death Medication: mirtazapine | No ECG Clinical examination | Unknown | Inflammatory changes in the heart | KCNQ1 p. Q220K | 1 neg (adopted) | LQTS |
2 | 8 | F | Sleep | Found deceased at home Not witnessed Infection | Healthy | None | None | Normal heart | KCNQ1 p. H240R | 3 pos/1 neg | LQTS |
3 | 18 | M | Unknown | Found deceased on the floor at home Not witnessed | Had a drinking problem Medication: alprazolam, alimemazine. Had a cold 2 weeks before death | None | None | Normal heart. Ethanol in femoral blood (1.06‰), alprazolam, alimemazine in therapeutic concentrations | KCNQ1 p. A370V | 4 pos/3 neg | LQTS |
4 | 14 | M | Sitting | Collapsed in school Witnessed | ADHD medication: tomoxetine | None | Unknown | Normal heart | KCNH2 p. S668L | None (adopted) | LQTS |
5 | 18 | M | Physical activity | Collapsed at the bus stop Witnessed | Cardiac arrest 3 years before death High blood pressure Fever spells in childhood and suspected seizures as teenager | ECG, cardiac ultra sound and EEG normal | Sister, grand grandfather and grand uncle SUD | Normal heart | RYR2 p. S4168T | 3 pos/3 neg | CPVT |
6 | 14 | M | Physical activity | Drowning Not witnessed | Healthy | None | None | Normal heart | RYR2 p. D401G De novo | 3 neg | CPVT |
7 | 18 | M | Sleep | Found deceased at home Not witnessed | Tachycardia 1½ years before death | None No ECG | None | Normal heart | None | – | Causa mortis ignota |
8 | 17 | M | Sleep/rest | Found deceased at home Not witnessed | Seizure 1 week before death Had a cold 3 weeks before death | No ECG | None | Normal heart | None | – | Causa mortis ignota |
9 | 2 | M | Sleep | Found deceased at home Not witnessed | 1 year before death sudden un-consciousness and falling from a bobby car | None | None | Normal heart | None | – | Causa mortis ignota |
10 | 3 | M | Sleep | Found deceased at home Not witnessed | Infection the day before death, fever seizures earlier | None | Father seizure, grandfather SUD | Normal heart | None | – | Causa mortis ignota |
11 | 18 | M | Sleep | Found deceased at home Not witnessed | Vomiting and palpitations some days before death | None | None | Normal heart | None | – | Causa mortis ignota |
12 | 17 | F | Sleep/rest | Found deceased at home Not witnessed | Vomiting, headache, and dizziness during the night before death | None | None | Normal heart | None | – | Causa mortis ignota |
13 | 18 | M | Sleep | Found deceased at home Not witnessed | The night before death vomiting, and hard physical activity | None | None | Normal heart In urine: metandienon; 945 ng/ul | None | – | Causa mortis ignota |
14 | 17 | M | Sleep | Found deceased at home Not witnessed | Diabetes | None | None | Normal heart, glucose, and lactate normal concentrations | None | – | Causa mortis ignota |
15 | 22 | F | Driving | Car accident Included because no injury that could explain the death | Pregnant | None | None | Normal heart | None | – | Causa mortis ignota |
Genetic testing of ion channel genes and clinical description of cases
Gene | Exon | Nucleotide change | Amino acid change | Region | Domain | Polyphen-2a
| SIFT | MutationTasterb
| Align-GVGDc
|
---|---|---|---|---|---|---|---|---|---|
KCNQ1
| 4 | c.658C>A | p. Gly220Lys | S3-S4 | Ion transport | Possibly damaging | Tolerated | Disease causing | C0 |
5 | c.719A>G | p. His240Arg | S4 | Ion transport | Benign | Deleterious | Disease causing | C25 | |
8 | c.1109C>T | p. Ala370Val | C-term | – | Probably damaging | Deleterious | Disease causing | C65 | |
KCNH2
| 8 | c.2003C>T | p. Ser668Leu | S6 | Probably damaging | Deleterious | Disease causing | C65 | |
RYR2
| 14 | c.1202A>G | p. Asp401Gly | N-term | MIR motif | Possibly damaging | Deleterious | Disease causing | C65 |
90 | c.12502T>A | p. Ser4168Thr | Cytosol | – | Possibly damaging | Deleterious | Disease causing | C55 |