Atrial fibrillation (AF) represents the most frequent form of sustained cardiac rhythm disturbance, affecting approximately 1% of the general population worldwide, and confers a substantially enhanced risk of cerebral stroke, heart failure, and death. Increasing epidemiological studies have clearly demonstrated a strong genetic basis for AF, and variants in a wide range of genes, including those coding for ion channels, gap junction channels, cardiac structural proteins and transcription factors, have been identified to underlie AF. Nevertheless, the genetic pathogenesis of AF is complex and still far from completely understood. Here, whole-exome sequencing and bioinformatics analyses of a three-generation family with AF were performed, and after filtering variants by multiple metrics, we identified a heterozygous variant in the ISL1 gene (encoding a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling), NM_002202.2: c.481G > T; p.(Glu161*), which was validated by Sanger sequencing and segregated with autosome-dominant AF in the family with complete penetrance. The nonsense variant was absent from 284 unrelated healthy individuals used as controls. Functional assays with a dual-luciferase reporter assay system revealed that the truncating ISL1 protein lost transcriptional activation on the verified target genes MEF2C and NKX2-5. Additionally, the variant nullified the synergistic transactivation between ISL1 and TBX5 as well as GATA4, two other transcription factors that have been implicated in AF. The findings suggest ISL1 as a novel gene contributing to AF, which adds new insight to the genetic mechanisms underpinning AF, implying potential implications for genetic testing and risk stratification of the AF family members.

心房颤动（AF）是持续性心律失常的最常见形式，影响了全世界约1％的普通人群，并大大增加了脑卒中，心力衰竭和死亡的风险。越来越多的流行病学研究清楚地证明了AF的强大遗传基础，并且已经确定了广泛的基因变异，包括编码离子通道，间隙连接通道，心脏结构蛋白和转录因子的那些，是AF的基础。然而，房颤的遗传发病机制是复杂的，仍然远未完全了解。在这里，我们对具有AF的三代家族进行了全外显子测序和生物信息学分析，并通过多种指标过滤了变体之后，我们确定了ISL1基因（编码对胚胎心脏发生和出生后心脏重塑至关重要的转录因子），NM_002202.2：c.481G> T；p。（Glu161 *），已通过Sanger测序验证，并以常染色体显性遗传家族中常染色体显性AF分离。284个无亲缘关系的健康个体不存在无意义的变异。使用双荧光素酶报告基因检测系统进行的功能检测显示，截短的ISL1蛋白在已验证的靶基因MEF2C和NKX2-5上失去了转录激活。此外，该变体使ISL1和TBX5以及GATA4之间的协同反式激活无效，GATA4是与AF相关的另外两个转录因子。研究结果提示ISL1 作为有助于AF的新基因，它为AF的遗传机制增添了新见解，暗示了对AF家族成员的基因检测和风险分层的潜在意义。