Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family

Abstract

MYPBC3 and MYH7 are the most frequently mutated genes in patients with hereditary HCM. Homozygous and compound heterozygous genotypes generate the most severe phenotypes. A 35-year-old woman who was a homozygous carrier of the p.(Pro1066Arg) variant in the MYBPC3 gene, developed HCM phenocopy associated with left ventricular noncompaction and various degrees of conduction disease. Her father, a double heterozygote for this variant in MYBPC3 combined with the variant p.(Gly1931Cys) in the MYH7 gene, was affected by HCM. The variant in MYBPC3 in the heterozygosis-produced phenotype was neither in the mother nor in her only sister. Familial segregation analysis showed that the homozygous genotype p.(Pro1066Arg) was located in a region of 26 Mb loss of heterozygosity due to some consanguinity in the parents. These findings describe the pathogenicity of this variant, supporting the hypothesis of cumulative variants in cardiomyopathies, as well as the modulatory effect of the phenotype by other genes such as MYH7. Advancing HPO phenotyping promoted by the Human Phenotype Ontology, the gene-disease correlation, and vice versa, is evidence for the phenotypic heterogeneity of familial heart disease. The progressive establishment of phenotypic characteristics over time also complicates the clinical description.

Keywords: HPO terms; MYBPC3; MYH7; cardiac phenotype; region of homozygosity.

Figure 1

(a) Echocardiographic study in the affected daughter, (b) magnetic resonance imaging report of the affected daughter.

Figure 2

Electrocardiographic study of the daughter (a) and her father (b) at the ages of 36 and 60 years, respectively. Abnormal ECGs: (a) Sinus rhythm with occasional premature ventricular complexes. T-wave abnormality, possible inferior ischemia, possible right ventricular hypertrophy, left atrial enlargement. (b) Sinus rhythm, RSR (OR) in lead V1/V2, coincident with ventricular conduction delay. Left ventricular hypertrophy with abnormal repolarization. Possible left atrial enlargement. Moderate left-axis deviation.

Figure 3

Family tree showing the segregation analysis of the two potential deleterious variants identified.

Figure 4

Visualization of the two identified variants, MYBPC3 (left side) and MYH7 (right side) by using the Integrative Genomics Viewer (IGV; https://software.broadinstitute.org/software/igv/ (accessed on 20 May 2022)). Samples are indicated at the left side of each picture. As a measure of variant quality, the number of reads and percentage of each nucleotide are shown in a window for each case.

Figure 5

The images describe the distribution of the variants of the exome trio analysis, the order being father, mother and patient. The left plot visualizes the variant distribution on chromosome 11, pointing out the detected ROH event on the 11:33902593–60531264 region (red frame). On the vertical axis the variant frequency on each sample is identified, whereas the horizontal axis describes the position in the GRCh37 reference genome. On the right, a histogram describing the distribution of the variants in the region is shown.