Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation

Abstract

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies

“…(Arg891Alafs ∗ 160) variant and showing different phenotypic evolution of heart abnormalities. This agrees with several reports showing different phenotypes from one family diagnosed with HCM due to a single pathogenic variant (Wang et al, 2018). In Family E, asymptomatic patients were young relatives, suggesting a delay in the onset of HCM that makes cardiac manifestations not yet evident at younger ages.…”

Left-ventricular outflow tract acceleration time is associated with symptoms in patients with obstructive hypertrophic cardiomyopathy

“…Contemporary literature divides HCM patients based on genetic status and phenotype, where the latter is defined primarily by the patient's maximal wall thickness and secondarily by the presence of an obstruction. This paradigm is largely incompatible with the vast heterogeneity observed in HCM cohorts concerning symptom severity and outcome, even in families [17][18][19][20]. A myriad of reasons explain the presence of symptoms in HCM, including LVOT obstruction, impaired filling secondary to diastolic dysfunction, microvascular dysfunction, the presence of arrhythmias, and, at a later stage, systolic dysfunction.…”

Radiomic Analysis of Native T1 Mapping Images Discriminates Between MYH7 and MYBPC3‐Related Hypertrophic Cardiomyopathy

“…Methods for genetic sequencing and in silico analysis were consistent with a previous report. 17 Exonenriched DNA was sequenced using a Hiseq2000 Sequencing System (Illumina, San Diego, CA). After sequencing, the raw data were saved in a FASTQ format.…”

“…20 These were further filtered using recommended threshold values (mapping quality >30, base quality >15, and read numbers >3). 17,20,21 Then SNVs available within dbSNP130 (hg19) as well as those reported by the 1000 Genomes Project, were filtered out from the output files using the ANNOVAR software tool. 22 Variant calling was performed separately for each individual sample.…”