200例肥厚型心肌病患者外显子组测序数据的重新分析：法国HYPERGEN队列初始分析5年后
Exome sequencing data reanalysis of 200 hypertrophic cardiomyopathy patients: the HYPERGEN French cohort 5 years after the initial analysis.
作者信息
Jaouadi Hager, Morel Victor, Martel Helene, Lindenbaum Pierre, de la Chapelle Lorcan Lamy, Herbane Marine, Lucas Claire, Magdinier Frédérique, Gilbert Habib, Schott Jean-Jacques, Zaffran Stéphane, Nguyen Karine
机构信息
Marseille Medical Genetics (MMG) U1251, Aix Marseille Université, INSERM, Marseille, France.
Department of Medical Genetics, La Timone Hospital, AP-HM, La Timone Children's Hospital, Marseille, France.
出版信息
Front Med (Lausanne). 2024 Oct 31;11:1480947. doi: 10.3389/fmed.2024.1480947. eCollection 2024.
BACKGROUND
Approximately half of hypertrophic cardiomyopathy (HCM) patients lack a precise genetic diagnosis. The likelihood of identifying clinically relevant variants increased over time.
METHODS
In this study, we conducted a gene-centric reanalysis of exome data of 200 HCM cases 5 years after the initial analysis. This reanalysis prioritized genes with a matched HCM entry in the OMIM database and recently emerging HCM-associated genes gathered using a text mining-based literature review. Further classification of the identified genes and variants was performed using the Clinical Genome Resource (ClinGen) resource and American College of Medical Genetics and Genomics (ACMG) guidelines to assess the robustness of gene-disease association and the clinical actionability of the prioritized variants.
RESULTS
As expected, the majority of patients carried variants in and M genes, 26% ( = 51) and 8% ( = 16), respectively, in accordance with the initial analysis. The vast majority of pathogenic (P) and likely pathogenic (LP) variants were found in (22 out of 40 variants) and (8 out of 16 variants) genes. Three genes-not included in the initial analysis-were identified: , , and . Considering only patients with unique variants in the last three genes, there was a 9% enhancement in variant identification. Importantly, variant carriers presented apical and septal HCM, aortopathies, and severe scoliosis for one patient. Ten patients (5%) carried variants in the gene, six in hotspot regions (exons 12 and 15). We identified seven variants within the gene in 12 patients (6%). Homozygous variants were detected in 2.5% of the cohort in ( = 1), ( = 1), and ( = 3) genes.
CONCLUSION
Our study revealed that no variants were found in the , , and genes in the HYPERGEN cohort. However, we identified variants in five out of the eight HCM core genes, with a high prevalence in young patients. We identified variants in three recent HCM-associated genes (, , and ) in 35 patients, with 18 patients carrying unique variants (9%). Our results further emphasize the usefulness of exome data reanalysis, particularly in genotype-negative patients.
背景
大约一半的肥厚型心肌病（HCM）患者缺乏精确的基因诊断。随着时间的推移，识别临床相关变异的可能性增加。
方法
在本研究中，我们在初始分析5年后对200例HCM病例的外显子组数据进行了以基因为中心的重新分析。该重新分析优先考虑在OMIM数据库中有匹配的HCM条目以及通过基于文本挖掘的文献综述收集的最近出现的HCM相关基因。使用临床基因组资源（ClinGen）和美国医学遗传学与基因组学学会（ACMG）指南对鉴定出的基因和变异进行进一步分类，以评估基因-疾病关联的稳健性和优先变异的临床可操作性。
结果
正如预期的那样，根据初始分析，大多数患者携带MYBPC3和MYH7基因的变异，分别为26%（n = 51）和8%（n = 16）。绝大多数致病性（P）和可能致病性（LP）变异在MYBPC3（40个变异中的22个）和MYH7（16个变异中的8个）基因中被发现。鉴定出三个初始分析中未包括的基因：TNNT2、TNNI3和TTN。仅考虑后三个基因中具有独特变异的患者，变异识别率提高了9%。重要的是，MYBPC3变异携带者表现为心尖和室间隔HCM、主动脉病变，且有一名患者患有严重脊柱侧凸。10名患者（5%）携带MYH7基因的变异，其中6名在热点区域（外显子12和15）。我们在12名患者（6%）中鉴定出MYL2基因内的7个变异。在队列的2.5%中检测到TTN、FLNC和ACTC1基因的纯合变异，分别为1例、1例和3例。
结论
我们的研究表明，在HYPERGEN队列中，TTN、FLNC和ACTC1基因未发现变异。然而，我们在8个HCM核心基因中的5个中鉴定出变异，在年轻患者中患病率很高。我们在35名患者中鉴定出3个最近的HCM相关基因（TNNT2、TNNI3和TTN）中的变异，其中18名患者携带独特变异（9%）。我们的结果进一步强调了外显子组数据重新分析的有用性，特别是在基因型阴性患者中。
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