PDF(Pubmed)
Abstract：
UNASSIGNED: FLNC encodes for filamin-C, a protein expressed in Z-discs of cardiac and skeletal muscle, involved in intracellular signalling and mechanical stabilization. Variants can cause diverse phenotypes with skeletal (myofibrillar or distal myopathy) and/or cardiac (hypertrophic, restrictive, and arrhythmogenic cardiomyopathies) manifestations. Truncating variants have recently been implicated in arrhythmogenic cardiomyopathy (ACM) without skeletal disease.
UNASSIGNED: Retrospective review of medical records, including cardiac investigations, was performed for families attending a specialized clinic with a FLNC truncating variant (FLNCtv). Variants were classified according to accepted variant interpretation criteria. Of seven families identified, six had primary cardiac phenotypes with one nonsense and five frameshift variants (nonsense-mediated decay competent) identified. One family had no cardiac phenotype, with a pathogenic variant (p.Arg2467Alafs*62) identified as secondary genetic finding. Of the six with cardiac phenotypes, proband age at diagnosis ranged 27-35 years (four females). Five families experienced sudden cardiac death (SCD) of a young relative (age range: 30-43 years), and one patient listed for cardiac transplant. Left ventricular (LV) ejection fraction ranged from 13 to 46%, with LV fibrosis (late gadolinium enhancement) on cardiac imaging or on postmortem histology seen in three families. Two families had one genotype-positive/phenotype-negative relative.
UNASSIGNED: The FLNCtv causes a left-sided ACM phenotype with a high risk of severe cardiac outcomes including end-stage heart failure and SCD. Incomplete penetrance is observed with implications for reporting secondary genetic findings.
UNASSIGNED: Retrospective review of medical records, including cardiac investigations, was performed for families attending a specialized clinic with a FLNC truncating variant (FLNCtv). Variants were classified according to accepted variant interpretation criteria. Of seven families identified, six had primary cardiac phenotypes with one nonsense and five frameshift variants (nonsense-mediated decay competent) identified. One family had no cardiac phenotype, with a pathogenic variant (p.Arg2467Alafs*62) identified as secondary genetic finding. Of the six with cardiac phenotypes, proband age at diagnosis ranged 27-35 years (four females). Five families experienced sudden cardiac death (SCD) of a young relative (age range: 30-43 years), and one patient listed for cardiac transplant. Left ventricular (LV) ejection fraction ranged from 13 to 46%, with LV fibrosis (late gadolinium enhancement) on cardiac imaging or on postmortem histology seen in three families. Two families had one genotype-positive/phenotype-negative relative.
UNASSIGNED: The FLNCtv causes a left-sided ACM phenotype with a high risk of severe cardiac outcomes including end-stage heart failure and SCD. Incomplete penetrance is observed with implications for reporting secondary genetic findings.
摘要：
■FLNC编码filamin-C，在心肌和骨骼肌的Z-椎间盘中表达的蛋白质，参与细胞内信号传导和机械稳定。变异可导致骨骼（肌原纤维或远端肌病）和/或心脏（肥厚，限制性的,和心律失常性心肌病）的表现。最近，截短变体与无骨骼疾病的心律失常性心肌病（ACM）有关。
■病历回顾性审查，包括心脏检查,为使用FLNC截断变体（FLNCtv）参加专门诊所的家庭进行。根据公认的变体解释标准对变体进行分类。在确定的七个家庭中，六个具有主要的心脏表型，其中一个无义和五个移码变体（无义介导的衰变能力）被鉴定。一个家族没有心脏表型，具有致病性变体（p。Arg2467Alafs*62）被鉴定为次要遗传发现。在六种有心脏表型的人中，诊断时的先证者年龄为27-35岁(4名女性).五个家庭经历了一个年轻亲戚的心脏猝死（SCD）（年龄范围：30-43岁），还有一名患者被列入心脏移植名单.左心室（LV）射血分数为13％至46％，在三个家庭中可见的心脏成像或死后组织学上的LV纤维化（晚钆增强）。两个家族有一个基因型阳性/表型阴性亲戚。
■FLNCtv导致左侧ACM表型，具有严重心脏后果的高风险，包括终末期心力衰竭和SCD。观察到不完整的外显率，对报告次要遗传发现有影响。
■病历回顾性审查，包括心脏检查,为使用FLNC截断变体（FLNCtv）参加专门诊所的家庭进行。根据公认的变体解释标准对变体进行分类。在确定的七个家庭中，六个具有主要的心脏表型，其中一个无义和五个移码变体（无义介导的衰变能力）被鉴定。一个家族没有心脏表型，具有致病性变体（p。Arg2467Alafs*62）被鉴定为次要遗传发现。在六种有心脏表型的人中，诊断时的先证者年龄为27-35岁(4名女性).五个家庭经历了一个年轻亲戚的心脏猝死（SCD）（年龄范围：30-43岁），还有一名患者被列入心脏移植名单.左心室（LV）射血分数为13％至46％，在三个家庭中可见的心脏成像或死后组织学上的LV纤维化（晚钆增强）。两个家族有一个基因型阳性/表型阴性亲戚。
■FLNCtv导致左侧ACM表型，具有严重心脏后果的高风险，包括终末期心力衰竭和SCD。观察到不完整的外显率，对报告次要遗传发现有影响。
