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Case Reports
. 2021 Aug 31;144(9):754-757.
doi: 10.1161/CIRCULATIONAHA.120.048295. Epub 2021 Aug 30.

New Variant With a Previously Unrecognized Mechanism of Pathogenicity in Hypertrophic Cardiomyopathy

Yasmine Aguib #  1   2 , Mona Allouba #  1   2 , Roddy Walsh #  3 , Ayman M Ibrahim  1   4 , Sarah Halawa  1   5 , Alaa Afify  1 , Mohammed Hosny  1   6 , Pantazis I Theotokis  2 , Aya Galal  1 , Sara Elshorbagy  1 , Mohamed Roshdy  1 , Heba S Kassem  7 , Amany Ellithy  1 , Rachel Buchan  2   8 , Nicola Whiffin  2   8   9 , Shehab Anwer  1 , Stuart A Cook  10   11   12 , Ahmed Moustafa  5   13 , Ahmed ElGuindy  1   2 , James S Ware #  2   8   12 , Paul J R Barton #  2   8   12 , Magdi Yacoub #  1   2   14
Affiliations
Case Reports

New Variant With a Previously Unrecognized Mechanism of Pathogenicity in Hypertrophic Cardiomyopathy

Yasmine Aguib et al. Circulation. .
No abstract available

Keywords: cardiomyopathy; codon, nonsense; frameshift mutation; genetic variation; high-throughput nucleotide sequencing; hypertrophic.

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Figures

Figure.
Figure.
A frameshift variant in MYH7 (c.5769delG) is associated with HCM. A, Left, MYH7 (c.5769delG) segregates with hypertrophic cardiomyopathy (HCM) in a large Egyptian family (limit of detection, 3.01). The proband is marked with an arrow. Ages of family members at diagnosis are shown. The variant segregated in all affected family members. Right, Clinical and genetic characteristics of the proband and affected family members depicted in the pedigree. Clinical history at presentation for patients with HCM. V.1: dyspnea, New York Heart Association (NYHA) class III, palpitations, and myectomy; IV.2: dyspnea, NYHA class II, and palpitations; IV.3: dyspnea, NYHA class II, and presyncope; IV.4: dyspnea, NYHA class III, and angina; IV.9: dyspnea, NYHA class II, paroxysmal nocturnal dyspnea, and myectomy; IV.10: dyspnea, NYHA class II, angina, palpitations, and myectomy; and IV.12: dyspnea, NYHA class III, angina, palpitations, and myectomy. Cardiac magnetic resonance (CMR) data were not available for V.2, V.4, IV.6, II.1, IV.2, and IV.3. B, Proband (ie, V.1 in pedigree) showing classic HCM features assessed by echocardiography and CMR. Top left and top right, Severe asymmetrical septal hypertrophy (basal interventricular septum measuring 36 mm) with systolic anterior motion of the mitral valve (bottom left) causing a peak systolic gradient of 50 mm Hg across the left ventricular outflow tract at rest (bottom right). C, Left, Histological characterization of HCM myectomy tissues (proband: V.1 and affected family members IV.9, IV.10, IV.12) compared with control myocardial tissues, stained with hematoxylin and eosin (H&E), picrosirius red (PSR), transforming growth factor-β1 (TGFβ1) immunohistochemistry, and wheat germ agglutinin (WGA). Scale bars are 20 µm. Right, WGA quantification in control subjects vs patients with HCM (PFisher<0.004, unpaired t test). D, RNA sequencing analysis of human heart tissue from the proband confirms the presence of both wild-type (WT; blue asterisk) and mutant (black asterisk) transcripts. MYH7 is on the reverse strand. E, Schematic of the MYH7 frameshift variant (MYH7fs) is predicted to lead to expression and translation of a truncated peptide. The cDNA sequence and predicted resulting amino acid sequence are shown for WT (top) and variant MYH7 (bottom) alleles. The frameshift variant (deletion of nucleotide C in exon 39) is predicted to result in an nonsense mediated decay–incompetent premature termination codon downstream of the last exon-exon junction. F, Left, Differentially expressed genes in RNA sequencing in left ventricular tissue from patients with MYH7fs, MYH7 rare missense variants (p.A355V, p.M690V, and p.D1208H), and control subjects. Each row and column in the heat map represent a differentially expressed gene and sample. Samples and genes are clustered according to the correlation among the genes and among the samples, respectively. The expression values are color-coded and scaled for each gene (ie, by row). Principal component (PC) analysis of gene signature of patients with HCM with the c.5769delG variant, patients with HCM with different rare missense MYH7 variants, and control subjects (inset). Right, Enrichment analysis of differentially expressed Gene Ontology terms in patients with HCM with the c.5769delG variant and controls. Enriched pathways (top) and diseases (bottom) that were downregulated in samples with MYH7 c.5769delG compared with controls.
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