Table 1.
Summary of the clinical and molecular information for our patients and previously reported individuals from the literature grouped by (A) Timothy syndrome phenotype and (B) Brugada syndrome phenotype. GRCh37/hg19 assembly and NM_000719.6 was used as the reference sequence for all variants with the exception of NM_001167625.1 for (c.1216G>A, p.G406R)
| Nucleotide (c.) | Amino Acid (p.) | Exon | Inheritance | Clinical Phenotype | |
|---|---|---|---|---|---|
| A. Timothy Syndrome | |||||
| Patient 1 | 4087G>A | V1363M | 33 | De Novo | Early onset intractable epilepsy, GDD, hypotonia, dysmorphic features, laryngomalacia, syndactyly, camptodactyly, anal stenosis |
| Patient 2 | 3717+1_3717+2insA | N/A | Intron 28 | PI | TOF, severe LVNC and heart failure, syndactyly, dysmorphic features |
| Patient 3 | 3717+1_3717+2insA | N/A | Intron 28 | Unknown | VSD, generalized adult-onset epilepsy, and ID |
| Splawski 2005 | 1216G>A | G406R | 8A | De novo | 13 individuals with classic Timothy syndrome |
| Corona-Rivera 2015 | 1216G>A | G406R | 8A | De novo | Fetal hydrops due to congenital AV block, postnatal prolonged QTc, SCA |
| Sepp 2017 | 1216G>A | G406R | 8A | De novo | No syndactyly with QT prolongation and AV conduction abnormalities |
| Etheridge 2011 | 1216G>A | G406R | 8A | Mosaic | Father (mosaic) with mild phenotype: syndactyly and prolonged QTc and a severely affected child Unrelated child (mosaic) with prolonged QTc, SCA due to VF, syndactyly |
| Splawski 2004, 2005* | 1216G>A* | G406R* | 8* | De novo/ mosaic |
De novo: Severe prolong QT, arrhythmias, sudden cardiac death, and cognitive delays; no syndactyly Mosaic: Two affected sibs with an “unaffected” mother |
| Splaswki 2005 | 1204G>A | G402S | 8 | De novo | Atypical Timothy syndrome, isolated QTc prolongation and arrhythmias, no syndactyly |
| Gillis 2012 | 4418C>G | A1473G | 36 | De novo | Stroke, early onset intractable epilepsy, GDD, joint contractures, dysmorphic facial features, syndactyly, cortical blindness, and myopathy |
| Wemhöner 2015 | 3497T>C | I1166T | 27 | De novo | 1 individual with HCM, syndactyly, ductus arteriosus, SCA |
| Boczek 2015 | 1552C>T | R518C | 12 | Inherited | 3 families with LQTS, HCM, SCA, congenital heart defects |
| B. Brugada Syndrome | |||||
| Antzelevitch 2007 | 116C>T | A39V | 2 | Inherited | SCA, short QT interval |
| 1468G>A | G490R | 10 | Inherited | SCA, short QT interval | |
| Fukuyama 2014 | 1141C>T | P381S | 8 | PI | LQTS |
| 1368G>A | M456I | 9 | Presumed de novo | ||
| 1745C>A | A582D | 13 | MI | ||
| 2573G>A | R858H | 19 | MI | ||
| 5347G>T | G1783C | 42 | De novo | ||
| Wemhöner 2015 | 82G>A | A28T | 2 | PI | LQTS |
| 2578C>G | R860G | 19 | De novo | SCA, LQTS | |
| 3496A>G | I1166V | 27 | Inherited | LQTS, Syncope | |
| 4425C>G | I1475M | 36 | MI | SCA, LQTS | |
| 4486G>A | E1496K | 36 | De novo | SCA, LQTS | |
| Liu 2017 | 5747A>G | Q1916R | 45 | Inherited | SCA due to early repolarization syndrome |
Abbreviations: GDD: Global Developmental delay; Het: Heterozygous; LQTS: Long QT Syndrome; Maternally Inherited: MI; Paternally Inherited: PI; SCA: Sudden cardiac arrest
*
which leads to an alternatively spliced product.