Table 1 Summary of 18 genes associated with autosomal recessive CM with robust evidence

From: Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Gene

Gene function

Phenotype

Reports

Families

Biallelic cases

Variant classes

Evidence summary

GWAS associations

Mouse knockout phenotypes

ALPK3

Localization of myomesin (M-band and nucleus)

DCM/HCM

9 (refs. 11,52,53,54,55,56,57,58,59)

17

26

PTV/missense

Exome (8 trio, 5 proband). Panel (2 trio, 2 proband). Max LOD = 2.9 (ref. 52)

HCM, LV/ECG traits

HCM and DCM features

BAG5

Co-chaperone of proteostasis regulation

DCM

2 (refs. 60,61)

5

6

PTV

Exome (3 trio, 2 proband)

–

LV dilation and arrhythmogenicity

CAP2

Thin filament protein (actin regulation)

DCM

3 (refs. 62,63,64)

3

4

PTV

Exome (2 trio, 1 proband). Max LOD = 1.9 (ref. 62)

–

Severe DCM, conduction anomalies, sudden death

FBXO32

E3 ubiquitin ligase subunit

DCM

2 (refs. 65,66)

2

6

Missense

Exome (2 trio). Max LOD = 3.4 (ref. 65)

HCM, AF, ECG traits

–

FLII

Actin remodeling protein

DCM

2 (refs.10,67)

3

3

PTV/missense

Exome (3 trio)

–

Embryonic lethality

JPH2

Junctional membrane complex

DCM

6 (refs. 7,8,10,68,69,70)

7

7

PTV/missense

Exome (2 trio, 2 proband). Panel (1 trio, 2 proband)

–

Embryonic lethality

KLHL24

E3 ubiquitin ligase substrate adapter

HCM

3 (refs. 10,71,72)

4

9

PTV/missense

Exome (3 trio, 1 proband). Max LOD = 3.6 (ref. 71)

–

–

LDB3

Z-disc protein

DCM

1 (ref. 73)

5

5

PTV

Exome (5 trio)

ECG traits

Severe DCM, early death

LEMD2

Inner nuclear membrane protein

ACM

1 (ref. 74)

2

11

Missense

Exome (2 large pedigrees). Max LOD = 7.3 (estimated)74

–

DCM-like phenotype with fibrosis and arrhythmia (p.Leu13Arg knock-in)

LMOD2

Thin filament protein (actin elongation)

DCM

5 (refs. 75,76,77,78,79)

5

6

PTV

Exome (4 trio). Panel (1 trio)

–

DCM-like phenotype, early death

MYZAP

Intercalated disc protein

DCM

2 (refs. 80,81)

3

8

PTV

Exome (3 trio)

AF

TAC-induced hypertrophy, HF, increased mortality

NRAP

Intercalated disc protein

DCM

10 (refs. 7,10,19,61,72,82,83,84,85,86)

30

32

PTV/missense

Exome (7 trio, 12 proband). Panel (2 trio, 9 proband).

RVAS: 1.9% versus 0% (P < 0.00001)19

ECG traits

–

PLEKHM2

Kinesin transport cargo adapter protein

DCM

2 (refs. 87,88)

2

5

PTV

Exome (1 trio). Panel (1 trio). Max LOD = 2.8 (estimated)87

LV traits

–

PPA2

Inorganic pyrophosphatase

DCM/SCD

7 (refs. 7,8,89,90,91,92,93)

32

53

Missense

Exome (21 trio, 3 proband). Panel (8 trio)

–

–

PPP1R13L

NF-κB and p53 inhibitor

DCM

6 (refs. 9,10,94,95,96,97)

11

15

PTV/missense

Exome (6 trio, 5 proband)

–

Severe and rapidly progressing DCM

RPL3L

Muscle-specific ribosomal protein

DCM

4 (refs. 10,98,99,100)

6

9

Missense

Exome (6 trio)

AF

–

SLC30A5

Zinc transporter

CM

1 (ref. 101)

2

4

PTV

Exome (2 trio)

–

Sudden death (60%)

TRIM63

E3 ubiquitin ligase

HCM

6 (refs. 25,102,103,104,105,106)

28

32

PTV/missense

Panel (7 trio, 21 proband).

RVAS: 0.4% versus 0% (P = 0.0002)104, 2.1% versus 0% (P = 0.003)25

Strain, ECG traits

Severe hypertrophy (TAC or TRIM55 double-knockout)

  1. For the evidence summary, cases are summarized as ‘exome’ (variants detected with genome-wide methods of genome and exome sequencing) or ‘panel’ (sequencing of distinct sets of CM-associated genes only), and as ‘trio’ (confirmed recessive inheritance with heterozygous parents) or ‘proband’ (recessive inheritance not confirmed but likely). The summary also includes the maximum reported or estimated LOD scores for large family pedigrees and details of the RVAS enrichment analysis. See the Supplementary Text and Methods for further details and citations for this genetic evidence, GWAS associations and mouse knockout phenotypes. Strain, myocardial strain in longitudinal direction; TAC, transverse aortic constriction.
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