A Nonsynonymous Polymorphism in Semaphorin 3A as a Risk Factor for Human Unexplained Cardiac Arrest with Documented Ventricular Fibrillation

Abstract

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67–5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A I334V, VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A I334V (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A I334V. Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A I334V genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A I334V in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.

Long-Term Outcome of Patients Initially Diagnosed With Idiopathic Ventricular Fibrillation

“…Importantly, a negative genetic test result does not exclude a genetic origin of IVF because many novel variants associated with IVF have been detected, and not all novel mutations were included in our panel. 23,24 Because the yield of genetic testing in IVF patients is relatively low and variants of uncertain clinical significance may be found, the current expert consensus statement on primary inherited arrhythmia syndromes does not recommend routine screening of large gene panels. 1 The limited available data that address single-targeted gene testing based on phenotype show a heterogeneous yield of 9% to 47%.…”

Semaphorin Signaling in Cardiovascular Development

“…Recently, a genetic variant in the human SEMA3A gene was associated with unexplained cardiac arrest and ventricular arrhythmia (Nakano et al, 2013). A non-synonymous polymorphism (I334V, rs138694505A > G) was identified in the 10 th exon of the SEMA3A gene, and this variant was significantly more common in a cohort of 83 Japanese patients diagnosed with unexplained cardiac arrest than in 2,958 healthy controls.…”

“…Similar to Sema3a knockout mice, patients with this I334V variant have abnormal patterning of sympathetic nerves and sinus bradycardia. The I334V variant protein has reduced activity in a repulsion assay (Nakano et al, 2013). Vascular Patterning PlexinD1.…”

Semaphorins in cardiovascular medicine

“…The expression of SEMA3A in the border zone of the infarcted area reduces sympathetic hyper-innervation, decreasing the prolonged QT intervals and the inducibility of ventricular tachyarrhythmias. These models explain the recent report that unexplained cardiac arrest with documented ventricular fibrillation is characterized by a high incidence of a the single nucleotide polymorphism, resulting in the modified SEMA3A-I334 V [37]. Interestingly, SEMA3A-I334 V shows reduced in vitro neural chemorepulsive activity [37].…”