Table 12.
Genes implicated in sinus node disease (SND)
| Gene | Locus | Phenotype/syndrome | Protein (functional effect) | Frequency | ClinGen classification |
|---|---|---|---|---|---|
| Genes for isolated SND | |||||
| SCN5A | 3p22.2 | BrS1, SND, ASS, LQT3195,266,267 | Cardiac Na+ channel α subunit (Nav1.5) (loss-of-function, INa↓) | 1–10% | NA/major gene ‘Definitive’ for LQTS, BrS |
| HCN4 | 15q24.1 | Familial SND, ST, left ventricular non-compaction.268,269 | Hyperpolarization-activated cyclic nucleotide-gated K+ channel 4 (loss-of-function, If ↓) | 1–10% | NA/major gene |
| GNB2 | 7q22.1 | Familial SND270 | G-protein β subunit 2 (gain-of-function, IK, ACh↑) | <1% | NA/rare gene |
| KCNQ1 | 11p15.4 | SQTS, [LQT1], AFib, SND271,272 | K+ voltage-gated channel (subfamily Q, 1) (Kv7.1) (Gain-of-function, IKs↑) | <1% | NA/rare gene. ‘Definitive’ for LQTS |
| KCNJ5 | 11q24.3 | Familial SND273,274 | G-protein gated inwardly rectifying K+ (GIRK) channel 5 (Kv3.4) (Gain-of-function, IK, ACh↑) | <1% | NA/rare gene |
| RYR2 | 1q43 | CPVT, SND249,275 | Ryanodine receptor 2 (gain-of-function) | <1% | NA/rare gene ‘Definitive’ for CPVT |
| Genes for syndromal disorders with SND | |||||
| LMNA | 1q22 | DCM (CMD1A), Afib (Emery-Dreifuss muscular dystrophy 2/3, congenital muscular dystrophy, limb-girdle myopathy, familial lipodystrophy type 2, Hutchinson-Gilford progeria, and various other disorders)197,199,200 | Lamin A/C | 1–10% | NA/rare gene ‘Definitive’ for DCM |
| CACNA1D | 3p21.1 | + Inner ear deafness276,277 (neurodevelopmental disorders, autisms spectrum disorder with epilepsy; primary aldosteronism) | L-type calcium voltage-gated channel subunit alpha 1-D (Cav1.3) | () | NA/rare gene |
| GNB5 | 15q21.2 | + Developmental delay, speech defects, severe hypotonia, pathological gastro-oesophageal reflux, retinal disease278 | G-protein β subunit 5, (inhibitory G-protein signaling) | () | NA/rare gene |
| SGOL1 | 3p24.3 | CAID syndrome; cohesinopathy with chronic atrial and intestinal dysrhythmia279 | Nuclear protein for chromosome segregation | () | NA/rare gene |
| EMD | Xq28 | DCM, LVNC, AFib, Emery-Dreifuss muscular dystrophy (EMD)209,280 | Emerin | () | NA/rare gene |
Frequency: refers to mutation detection rate29; core genes: major (>10%) or minor (1–10%); rare gene (<1%); (): mutation rate unknown and/or single reports.
Other Phenotypes: […], phenotype associated with gene, but unlinked with SND.
ClinGen: Clinical Genome Resource of NCBI; https://clinicalgenome.org.
ASS, atrial stand still; AFib, atrial fibrillation; ASD, atrial septal defect; BrS, Brugada syndrome, CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; LQT, long-QT syndrome type; LVNC, left ventricular non-compaction cardiomyopathy; SND, sinus node dysfunction; ST, sinus tachycardia; X-chr., X-chromosomal.