Table 3. Variants with likely functional effects in the SUDI cases.
| Case | Sex | Age (months) | San Diego criteria1 | Nordic criteria12 | Risk factors | Gene | Function | Nucleotide | Amino acid | MAF in Danish population | MAFa | Evidence of pathogenicity |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 0 | II | 1 | 2, 3 | PRDM16 (NM_022114.3) | Proliferation of cardiomyocytes | c.2468G>C | p.(R823P) | − | 0.2% | Known disease-associated variants in exon |
| 2 | M | 2 | II | 1 | 3 | TRPM4 (NM_017636.3) | Calcium channel | c.1575G>A | p.(W525*) | 0.2% | 0.1% | Null variant |
| 3 | M | 2 | IB | 1 | 4 | ANK2 (NM_001148.4) | Channel-interacting | c.4373A>G | p.(E1458G) | 0.05% | 0.02% | Seen in LQTS family, functional evidence43 |
| 4 | F | 1 | II | 1 | 1 | KCNJ5 (NM_000890.3) | Potassium channel | c.148C>Tb | p.(R50C) | − | − | Known disease-associated variants in exon, assumed de novo |
| 5 | F | 1 | II | 1 | 7,9c | RYR2 (NM_001035.2) | Intracellular Ca2+ homeostasis | c.7099G>Ad | p.(G2367R) | − | 0.01% | Seen in ARVC patient44 |
| 6 | F | 2 | II | 1 | 3 | MYH6 (NM_002471.3) | Sarcomeric | c.756C>G | p.(H252Q) | − | − | Functional evidence45 |
| 7 | M | 1 | II | 1 | 2,3 | SLC22A5 (NM_003060.3) | Carnitine transporter | c.34G>A | p.(G12S) | − | 0.2% | Seen in CTD patient46 |
| RYR2 (NM_001035.2) | Intracellular calcium homeostasis | c.10742G>Ab | p.(R3581K) | − | − | Assumed de novo | ||||||
| 8 | M | 1 | II | 1 | 3 | LAMA4 (NM_001105206.2) | Cytoskeletal | c.1901T>Ab | p.(V634D) | − | − | Assumed de novo |
| 10 | M | 6 | II | 1 | 1 | DSG2 (NM_001943.3) | Desmosomal | c.1370C>Gb | p.(S457C) | − | − | Functional protein domain, assumed de novo |
| 11 | F | 0 | USID | 18 | 7 | TRPM4 (NM_017636.3) | Calcium channel | c.1294G>A | p.(A432T) | 0.05% | 0.1% | Seen in CCD family, functional evidence47 |
| TRPM4 (NM_017636.3) | Calcium channel | c.1744G>A | p.(G582S) | 0.05% | 0.1% | Seen in CCD patient48 | ||||||
| 13 | F | 1 | II | 1 | 2,3 | KCNJ5 (NM_000890.3) | Potassium channel | c.631C>T | p.(R211W) | − | 0.02% | Functional protein domain |
| RYR2 (NM_001035.2) | Intracellular calcium homeostasis | c.5614G>Ad | p.(D1872N) | 0.05% | − | Functional protein domain | ||||||
| 14 | M | 2 | II | 1 | 3 | PRDM16 (NM_022114.3) | Proliferation of cardiomyocytes | c.2576C>T | p.(S859L) | − | 0% | Functional protein domain |
| 15 | F | 1 | II | 1 | 2,3,8 | KCNE4 (NM_080671.3) | Potassium channel | c.380A>Gb | p.(E127D) | − | − | Assumed de novo |
| 16 | F | 1 | II | 1 | 3,9e | MYPN (NM_001256267.1) | Z-disc | c.662A>T | p.(D221V) | 0.05% | 0.2% | Known disease-associated variants in exon |
| 18 | F | 0 | USID | 18 | 9f | LDB3 (NM_001171610.1) | Z-disc | c.1691G>Ab | p.(R564Q) | − | − | Functional protein domain, assumed de novo |
| 24 | F | 0 | II | 1 | 3 | TAZ (NM_000116.3) | Mitochondrial | c.535C>Gb | p.(P179A) | − | − | Functional protein domain, assumed de novo |
Abbreviations: MAF: minor allele frequency in the Danish population,25 LQTS: long QT syndrome, ARVC: arrhythmogenic right ventricular cardiomyopathy, CTD: carnitine transporter deficiency, CCD: cardiac conduction disease.
Clinical data and classification of the SUDI cases with variants with likely functional effects. Included are details of the functions of the gene, nucleotide and amino acid changes, frequencies in healthy populations and evidence of pathogenicity.
The San Diego criteria: IA: SIDS (>21 days, <9 months, normal clinical history, normal growth/development, no similar deaths in siblings/close relatives, no suspicion regarding death scene investigation, absence of potentially pathological abnormalities at autopsy including toxicology, microbiology, radiologic, vitreous chemistry and metabolic screening); IB: death scene not investigated and/or ≥1 of following not performed: microbiology, radiologic, vitreous chemistry and metabolic screening; II: ≥1 of following not fulfilled: age range, death among siblings/close relatives, neonatal/perinatal conditions, mechanical asphyxia not excluded with certainty, abnormal growth/development, inflammatory changes/abnormalities not sufficient to be the cause of death. USID: Not fulfilling criteria for SIDS I or II.
The Nordic criteria: 1: unknown cause of death, infant. 2: Brain/neurological disorders. 3: Pulmonary/respiratory disorders. 4: Heart/vessel disorders. 5: Gastrointestinal disorders. 6: Sepsis. 7: Intoxication. 8: Unspecified systemic disorders. 9: Asphyxia, traumatic. 10: Asphyxia, drowning. 11: Asphyxia, other. 12: Severe trauma. 13–16: Trauma (13: neurological system, 14: respiratory system, 15: cardiovascular system, 16: gastrointestinal system). 17: Exsanguination. 18: Unknown cause of death. 19: Other systematic disorders. 20: Combustion. 21: Blood disorders. 22–26: Unspecified disorders (22: Neurological system, 23: Respiratory system, 24: Cardiovascular system, 25: Gastrointestinal system, 26: Urogenital system). 27: Urogenital disorders.
Risk factors/other symptoms: 1: Missing information of birth. 2: Preterm/prenatal problems solved. 3: Mechanical asphyxia cannot be excluded. 4: One or several investigations missing. 5: Age 0–21 days or 270–265 days. 6: Unexplained trauma/abuse/neglect/unintended trauma. 7: Similar cases in siblings, not suspected to be homicide or of genetic aetiology. 8: Pronounced inflammatory changes or abnormalities not sufficient to be cause of death. 9: Other. 10: Death scene investigation not performed.
Minor allele frequency in European-American population in NHLBI GO Exome Sequencing Project ESP17 or dbSNP18 was used.
Novel variant.
Not normal growth/development.
Previously identified by Larsen et al.7
Jaundice.
Home delivery, infant buried in backyard.