A Splice Variant of the MYH7 Gene Is Causative in a Family with Isolated Left Ventricular Noncompaction Cardiomyopathy

Figures

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  Figure 1. Pedigree of the family (created using the CeGaT Pedigree Chart Designer software v3.0, (CeGaT GmbH, Tübingen, Germany) [16]). Women are shown by circles and men by squares. Affected persons are shown by black figures, crossed figures indicate deceased people. The proband (III-4) is indicated by the arrow.

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  Figure 2. (A–C) The proband’s cardiac magnetic resonance imaging (cMRI) in cine mode, SSFP sequence: (A) long axis 2-chamber images, (B) long axis 4-chamber images, (C) short axis images at the level of the middle segments. (D–F) DE (delayed enhancement) cMRI images, inversion recovery (IR) sequence with suppression of the signal from the normal myocardium. No areas of contrast enhancement were detected, which indicates the absence of areas of intramyocardial fibrosis, scarring or inflammatory myocardial damage. * indicates a layer of non-compact myocardium in the apical segments, → indicates clefts in the middle anteroseptal segment.

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  Figure 3. Electropherograms confirmed NM_000257.4:c.895+1G>A in the genome of patients III-4 and II-5 and a wildtype sequence in III-5 and II-6.

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  Figure 4. Schematic representation of exonic structure of the coding sequence of the MYH7 gene (transcript NM_000257.4) and its predicted splicing alteration. Each polygon with a number in its center denotes the corresponding exon (exons 1 and 2 are non-coding in NM_000257.4). The shape of an exon border indicates the reading frame. In-frame exons are coloured grey and the rest are coloured yellow. Exon boundaries overtaking (+1 or −2) and lagging (−1 or +2) relative to the reading frame are shown as convex and concave, respectively. Polygons with bold contours represent the coding sequence of the myosin motor domain (exons 4-21). Orange stars indicate the sites of actin binding. (A): normal gene product. (B): predicted product with the variant t.NM_000257.4:c.895+1G>A; g.hg38.chr14:23430900C>T which was found in the patient’s genome.

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  Figure 5. Schematic representation of how MYH7 participates in myosin assembly. The MYH7 gene product directly forms the myosin filament with actin-binding head. Normal functional proteins synthesized from wildtype MYH7 are colored red. Malfunctioning proteins from mutated (by dominant negative mechanism) MYH7 are colored green. (A) Normal formation of myosin filaments—synthesis of normal functional proteins from both copies of the MYH7 gene (B) Haploinsufficiency—synthesis of normal functional proteins from only one copy of the gene, the total amount of filaments decreases by half, though remaining myosin is all normal. (C) Dominant negative mechanism—synthesis of the proteins from both copies of MYH7, half proteins are misfolded and malfunctioning, and all filaments contain malfunctioning proteins.