Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
CIBERCV, Madrid, Spain.
Open Heart. 2021 Sep;8(2). doi: 10.1136/openhrt-2021-001789.
One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: p.Arg502Trp/Gln.
We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of c.2149-1G>A. Carriers with this mutation were compared with those from p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes.
c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups.
c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.
肥厚型心肌病（HCM）面临的挑战之一是确定遗传变异的致病性，并建立基因型/表型相关性。本研究旨在：（1）证明 c.2149-1G>A 是一个创始致病性变体；（2）描述突变携带者的表型和临床特征；（3）比较这些患者与最常见的致病性 HCM 变体：p.Arg502Trp/Gln。
我们回顾了在我们机构进行的 HCM 先证者的基因检测。我们进行了转录分析以证明剪接效应，并进行了单倍型分析以支持 c.2149-1G>A 的创始效应。携带该突变的患者与携带 p.Arg502Trp/Gln 的患者在表现特征、影像学和结果方面进行了比较。
在 570 个先证者和 25 个亲属中发现了 c.2149-1G>A。外显率取决于年龄和性别，36 岁以上携带者的 50.0%和 40 岁以上携带者的 75.0%出现 HCM。男性的外显率明显更高：在 30 岁以上的携带者中，100.0%的男性与 50.0%的女性出现 HCM 表型（p=0.01）。男性的诊断年龄也更年轻（32±13 岁 vs 53±10 岁，p<0.001）。c.2149-1G>A 导致异常转录，导致单倍体不足，并在两个单倍型中分离。然而，两者都来自一个创始单倍型。受影响的携带者的功能分级和左心室射血分数（LVEF）较高（两者均 p<0.05）。然而，两组之间的主要不良结局发生率相似。
c.2149-1G>A 剪接变体是一个创始突变。受影响的男性表现出早发性 HCM，且外显率高于女性。携带者的功能分级和 LVEF 高于 p.Arg502Trp/Gln 携带者，但主要不良结局发生率相似。
