A biallelic loss-of-function variant in MYZAP is associated with a recessive form of severe dilated cardiomyopathy.

PURPOSE: Dilated cardiomyopathy (DCM) is a primary disorder of the cardiac muscle, characterised by dilatation of the left ventricle and contractile dysfunction. About 50% of DCM cases can be attributed to monogenic causes, whereas the aetiology in the remaining patients remains unexplained. METHODS: We report a family with two brothers affected by severe DCM with onset in the adolescent period. Using exome sequencing, we identified a homozygous premature termination variant in the MYZAP gene in both affected sibs. MYZAP encodes for myocardial zonula adherens protein - a conserved cardiac protein in the intercalated disc structure of cardiomyocytes. RESULTS: The effect of the variant was demonstrated by light and electron microscopy of the heart muscle and immunohistochemical and Western blot analysis of MYZAP protein in the heart tissue of the proband. Functional characterization using patient-derived induced pluripotent stem cell cardiomyocytes revealed significantly lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction. CONCLUSION: We provide independent support for the role of biallelic loss-of-function MYZAP variants in dilated cardiomyopathy. This report extends the spectrum of cardiac disease associated with dysfunction of cardiac intercalated disc junction and sheds light on the mechanisms leading to DCM.

Clinicopathological Characteristics of BRAF V600E Mutated Melanomas in the Dalmatian Region of Croatia.

A high proportion of cutaneous melanomas harbor activating mutations of the BRAF or NRAS genes, which are components of mitogen-activated protein kinase (MAPK) signal transduction pathway. The importance of BRAF V600E mutation in melanoma is not only related to the possibility of the administration of the targeted therapy, but also to the fact that BRAF V600E mutated melanomas have distinct clinicopathological features. We investigated the clinicopathological features of 80 primary skin melanomas with known BRAF V600E mutation status excised in the Dalmatian region of Croatia, with comparison of these features between the mutated and wild-type group. The frequency of BRAF V600E mutation was 47.5%. In comparison with wild-type melanomas, BRAF V600E mutated melanomas were significantly associated with younger age and female sex (P=0.014 and P=0.011, respectively). The mutated melanomas were more often located on the extremities, of a nodular type, ulcerated, and with higher median of mitotic index but without significant difference in comparison with wild-type tumors. There were no differences in the depth of invasion and the presence of lymphovascular invasion, tumor infiltrating lymphocytes, and regression between the investigated groups. The frequency of BRAF V600E mutation in our cohort of primary skin melanomas and the clinicopathological features of mutated tumors were similar to those reported in the literature, except for the higher proportion of women observed in our group with mutation.