. 2022 Apr 4;24(8):1307–1367. doi: 10.1093/europace/euac030

Table 9.

Genes implicated in CCD/PCCD

Gene	Locus	Phenotype—syndrome	Protein (functional effect)	Frequency	ClinGen classification
Genes for isolated SND
SCN5A	3p22.2	BrS1, SND, ASS, (LQT3)^194–196,^203,²⁰⁴	Cardiac Na channel α subunit (Nav1.5) Loss-of-function, I_Na ↓	>10%	NA/major gene; definite for LQTS, BrS1
TRPM4	19q13.33	^205, ²⁰⁶	Transient receptor potential melastatin 4 channel Gain-of-function	1–10%	NA/major gene
Genes for syndromal disorders with CCD/PCCD
LMNA	1q22	DCM (CMD1A), AFib, SND (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	>10%	NA/major gene; definite for DCM
DES	2q35	DCM (CMD1I), ACM, Myofibrillar myopathy (MFM1)	Desmin	()	NA/rare gene; Definite for DCM, moderate for ACM
DMD	Xp21.2-p21.1	DCM (CMD3B), muscular dystrophy (Becker or Duchenne type)²⁰⁷	Dystrophin	()	NA/rare gene
DMPK	19q13.32	DCM, myotonic dystrophy (DM1)²⁰⁸	Myotonic dystrophy protein kinase	()	NA/rare gene
EMD	Xq28	DCM, LVNC, SND, Emery-Dreifuss muscular dystrophy (EMD)^209,²¹⁰	Emerin	()	NA/rare gene
LAMP2	Xq24	HCM, DCM, LVNCDanon disease (glycogen storage disease), skeletal muscle involvement, mental retardation²¹¹	Lysosomal-associated membrane protein 2	()	NA/rare gene; Definite for HCM
ZNF9	3q21.3	DCM, myotonic dystrophy (DM2)²¹²	Zink finger protein 9 (CZNP)	()	NA/rare gene
GLA	Xq22.1	Fabry disease (HCM, RCM, acral paresthaesia, PNP, kidney insufficiency, angio-keratoma, anhydrosis, cornea verticillata, etc.)	Galactosidase α	()	NA/rare gene; definite for HCM
PRKAG2	7q36.1	Cardiac preexcitation (WPW), LVH/HCM,²¹³	AMP-activated protein kinase γ2-subunit	()	NA/rare gene; definite for HCM
TNNI3K	1p31.1	DCM, AFIB²¹⁴	Troponin I-interacting MAP kinase	()	NA/rare gene
NKX2-5	5q35.1	ASD7, (VSD7, TOF)	Transcription factor Nkx2.5	()	NA/rare gene
GJC1	17q21.31	Bone malformations (brachyfacial pattern, finger deformity, and dental dysplasia)²¹⁵	Connexin 45	()	NA/rare gene
TBX5	12q24.21	Holt-Oram syndrome (HOS) (hand-heart syndrome): ASD, hand and limb malformation (e.g., triphalangeal thumb), other CHD	Transcription factor TBX5	()	NA/rare gene
MYL4	17q21.32	AFib/conduction disease	atrial-specific myosin light chain	()	NA, rare gene
mtDNA	Mitochondrial DNA	Kearns-Sayre syndrome (KSS): Ptosis, progressive external ophthalmoplegia, ataxia, retinitis pigmentosa; Chronic progressive external ophthalmoplegia (CPEO), ptosis²¹⁶	(37 mitochondrial genes)	()	NA/rare gene

Frequency: refers to mutation detection rate;²⁵ 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 CCD/PCCD.

ClinGen: Clinical Genome Resource of NCBI; https://clinicalgenome.org, NA: not available = not yet curated.

ACM, arrhythmogenic cardiomyopathy; AFib, atrial fibrillation; ASD, atrial septal defect; ASS, atrial stand still; BrS, Brugada syndrome, CHD, congenital heart disease, DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQT, long-QT syndrome subtype; LVH, left ventricular hypertrophy; LVNC, left ventricular non-compaction cardiomyopathy; PNP, polyneuropathy; WPW, Wolff–Parkinson–White syndrome; RCM, restrictive cardiomyopathy; SND, sinus node dysfunction; TOF, Tetralogy of Fallot; VSD, ventricular septal defect; X-chr., X-chromosomal.