背景:最近的外显子组测序研究确定丝状蛋白C(FLNC)是肥厚型心肌病(HCM)的候选基因。我们的目的是确定大量HCM患者中FLNC候选变异的比率,这些患者也对主要肌节基因进行了测序。
结果:对448例HCM患者的MYH7、MYBPC3、TNNT2、TNNI3、ACTC1、TNNC1、MYL2、MYL3、TPM1和FLNC基因进行了下一代测序(半导体芯片技术)。我们还对来自同一人群的450名健康对照进行了测序。根据报告的人口频率,生物信息学标准,和家庭隔离,我们在22例患者中鉴定出20个FLNC候选变异体(13个新变异体;1个无意义变异体;19个错义变异体).与患者相比,对照中只有1个错义变异未报告(P=0.007;Fisher精确概率检验).根据家族隔离和报道的功能研究,6的候选变异(在7例患者)最终被归类为可能的致病性,10作为不确定意义的变体,和4一样可能是良性的。
结论:我们为FLNC参与HCM的发展提供了令人信服的证据。大多数FLNC变体与轻度形式的HCM和降低的外显率有关,很少有家庭受到影响,以确认隔离。我们的工作,以及在扩张型和限制性心肌病患者中发现FLNC变异的其他人,指出该基因是结构性心肌病的重要原因。
BACKGROUND: Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes.
RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control\'s missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign.
CONCLUSIONS: We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.