Paediatric or syndromic cardiomyopathy

Gene: MYZAP

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 11:50 a.m. | Last Modified: 24 Feb 2025, 11:50 a.m.

Panel Version: 6.7

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Copied this gene from R132 Dilated and arrhythmogenic cardiomyopathy since NHS GMS reviewers suggest that it is more suited to be on the R135 Paediatric or syndromic cardiomyopathy panel.

Note the MYZAP gene is part of the GRINL1A complex transcription unit, or GCOM1 gene, which also includes the downstream POLR2M gene.

Helio et al. (2021) (PMID: 34899865) - 2 Finnish families with different homozygous variants in GCOM1 in affected individuals. Probands had either DCM or arrhythmogenic right ventricular cardiomyopathy (ARVC). Note in Family 1, one family member without the variant had DCM secondary to lymphocytic myocarditis. Age at diagnosis ranged from 24 to 41.

Maver et al. (2022) (PMID: 35840178) - 2 Slovenian brothers affected by severe DCM with onset at ages 14 and 16 years. Both had a homozygous premature termination variant in MYZAP.

Ochoa et al. (2024) (PMID: 38436102) - 2 sisters of Spanish ancestry with compound heterozygous variants in MYZAP and a severe form of DCM. Neither patient had extracardiac features. Both were diagnosed in their early 30s.

Created: 6 Dec 2024, 11:35 a.m. | Last Modified: 6 Dec 2024, 11:35 a.m.

Panel Version: 6.5

Comment on phenotypes: There is now an association with Cardiomyopathy in OMIM so added this as a phenotype term.

Created: 6 Dec 2024, 9:43 a.m. | Last Modified: 6 Dec 2024, 9:43 a.m.

Panel Version: 2.36

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. Reviewers suggest it is more suitable for R135 Paediatric or syndromic cardiomyopathy.

Created: 6 Dec 2024, 9:37 a.m. | Last Modified: 6 Dec 2024, 9:37 a.m.

Panel Version: 2.35

Comment on list classification: New gene added to the panel by Aleš Maver. MYZAP is not yet associated with any phenotype in OMIM or Gene2Phenoype. At least three unrelated families have been reported with biallelic LOF variants in MYZAP and a phenotype of DCM (PMIDs: 34899865; 35840178; 38436102). Studies in zebrafish and mice demonstrate the link between MYZAP and cardiomyopathy (PMIDs: 20093627; 24698889). Overall, the evidence is sufficient to promote this gene to Green at the next GMS panel update.

Created: 17 Apr 2024, 9:47 a.m. | Last Modified: 17 Apr 2024, 9:47 a.m.

Panel Version: 2.21

Comment on mode of pathogenicity: Changed from "Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments" to "Other". LOF does cause phenotype.

Created: 16 Aug 2022, 12:41 p.m. | Last Modified: 16 Aug 2022, 12:41 p.m.

Panel Version: 1.30

Red List (low evidence)

Two independent publications reported the presence of biallelic loss-of-function variants in MYZAP gene in three families altogether with recessive dilated cardiomyopathy (DCM) (PMID:34899865 and PMID:35840178). Altogether, 8 patients with DCM and biallelic LOF variants are reported in the three published families.
Functional studies published previously linked the loss of MYZAP protein to DCM in zebrafish (PMID:20093627).
Functional studies of the variant reported in PMID:35840178 have shown that the variant led to lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction in the patient-derived iPSC cardiomyocytes.
Sources: Other

Created: 11 Aug 2022, 8:32 a.m. | Last Modified: 11 Aug 2022, 8:39 a.m.

Panel Version: 1.28

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Dilated cardiomyopathy

Publications

• 34899865
• doi:10.1101/mcs.a006221

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments