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Cardiology Plus Dec 2016, Vol 1. No 4 14 Research RESEARCH ARTICLES One familial III degree atrioventricular block and its gene detection Jin-chun Zhang, Damin Huang, Zhaoxia Wang, XiaohanLuo, Jian Ji, Lei Song, Zhihua Li, Shuxin Hou, Caiwen Wei, Zengyan Zhao, Yingmin Lu * Department of Cardiology, Chongming branch of Shanghai Xinhua Hospital, ShangHai, 200072, China Abstract Objective: To investigate the genetic basis of a Chinese familial third degree atrioventricular block. Methods: The clinical data of all family members were collected, including physical examination, electrocardiogram and echocardiography. Exome sequencing was performed for all patients. Results: This family contains 22 members of which 6 are patients. Cardiac symptoms appeared at forty years of age, starting with second degree atrioventricular block eventually developing into third degree atrioventricular block. These 6 patients received permanent pacemaker implantation. The genetic pedigree suggested that the autosomal disorder may not be completely dominant. Compared with normal subjects, 24 different genes were detected in patients with familial atrioventricular block. Conclusion: This family is unambiguously affected by familial atrioventricular block caused by incomplete dominant inheritance of euchromosome, and another genetic mutations that may contribute to it. Key Words: Cardiology; Atrioventricular block; Arrhythmia; Family study; Gene mutation Complete atrioventricular block (AVB), also known as third- relatively rare and mainly related to gene mutations. Currently, degree AVB, is complete atrioventricular dissociation caused by two types of familial AVB have been proposed: a congenital type abnormally decreased conduction ability in the atrioventricular and an adult-onset type, both of which are autosomal dominant conduction system. In this condition, the impulse generated in genetic disorders. The former is relatively uncommon and can the atrium of the heart cannot propagate to the ventricles. AVB be seen at birth or during infancy. It is associated with very poor is more common in patients over 50 years old and can have prognosis and may be caused by maternal ribonucleoprotein multiple causes, most of which are secondary. Familial AVB is autoantibodies [1] . The latter has an onset in patients 30 to 50 years of age and is associated with various heart block phenotypes with symptoms ranging in severity. Adult-onset familial AVB is an incomplete autosomal dominant disease and can result in syncope or sudden death [2]. In this study, a pedigree Corresponding author : LU Yingmin. Department of Cardiology, investigation was conducted for a patient with familial AVB. chongming branch of shanghai xiahua hospital; Preliminary genetic detection studies were performed for the Email: [email protected] pedigree and the results are reported. Zhang et al III AVB block and gene detection 15 1 Data and Methods 1.1 Pedigree Investigation The family members and spouse of the proband were included. Medical histories were collected for the included respondents and examinations including physical examination of conventional systems, conventional 12-lead electrocardiogram (24-h ambulatory electrocardiogram if necessary) and cardiac ultrasound were performed. A family genetic map was generated (see Figure 1). Blood samples were collected from each included respondent into anticoagulant tubes, and the DNA was extracted for genetic studies. All procedures were agreed upon by pedigree investigators and all respondents signed informed consent forms. The investigation was discussed and justified by the medical ethics committee of Xinhua Hospital affiliated with the Shanghai Jiao Tong University School of Medicine. Figure 1 Family pedigree for familial atrioventricular block 1.2 Genetic Detection 1.2.1 Sample Collection electrocardiogram suggested second-degree atrioventricular 5 mL of venous blood was collected and transferred into block (AVB) and pre-excitation syndrome. The ambulatory anticoagulant tubes. The tubes were placed in a horizontal electrocardiogram also showed second-degree AVB and third- centrifuge and centrifuged at 3000 RPM for 20 minutes. After degree AVB in particular. Results of the heart echocardiography centrifugation, the mononuclear cell layer between the plasma indicated that measurement values for the four chambers of heart and erythrocytes was obtained and DNA extraction from were within the normal range, thickening of interventricular the mononuclear cells was performed. Blood genomic DNA septum (14 mm), a left ventricular ejection fraction of 67% and isolation kits (TRIzol® Reagent, Life Technologies) were used decreased left ventricular diastolic compliance. After admission, for DNA extraction according to the manufacturer’s instructions. the patient was given Xinbao pills and Salbutamol Sulfate to 1.2.2 Exome Sequencing increase heart rate, however no improvement was observed. A Through hybridization and enrichment of exon sequences, single chamber pacemaker (VVI) implantation was performed in low-quality reads were removed and the quantity of reads and our hospital and the pacemaker was later replaced in 2011 due to sequencing quality were summarized with quality control (QC). battery charge depletion. Short sequences were rapidly mapped to the genome, redundant Family history of the patient was further inquired and other reads from PCR amplification were removed by the rmdup tool, members in the family had similar diseases. Therefore, other multiple local sequence alignment was re-conducted and false members in the family were also investigated. Six members positives around indel were eliminated. in the family had the disease, which is shown in the family 1.2.3 Mutation Analysis pedigree (see Figure 1). The father of the proband received a The base qualities were re-graded and the bases were screened. VVI in Changhai Hospital, Shanghai in 1995 that was replaced Possible pathogenic gene mutations screened were verified by in our hospital in 2003. The younger brother of the proband real-time PCR. received a dual chamber pacemaker (DDD) in Renji Hospital, Shanghai in 2005. The elder brother of his father received a 2 Results VVI in our hospital in 2000. The younger male cousin received 2.1 Clinical Data had a prior medical history of bradycardia (unknown medical The 42-year-old male proband was admitted to the hospital history) and had received a pacemaker for treatment. a DDD in our hospital in 2003. The grandfather of the proband due to “chest tightness and palpitations for 3 days”. He had experienced these symptoms with occasional syncope in his 2.2 Mutant Gene Detection 30s without special treatment. After admission in 2003, the The mutant genes of patients in the family were detected by Cardiology Plus Dec 2016, Vol 1. No 4 16 exome sequencing and the alignment with the healthy Asian not have the disease, or are currently too young for its potential population was performed. 24 differential genes were found, onset. including KDELC2, SEC14L2, SEC31A, DNAH9, EPB41L2, Previous studies have reported that associated morbidity RFX8, KBTBD12, KLHL29, LRRC59, LRP5, MUC6, had a trend of familial aggregation, which suggested a gene OLFML2B, PLXNA3, KCNH6, SALL1, ARMCX4, SLC22A16, mutation. Possible causative genes (SCN5A, NKX2.5 and STON2, TTF1, TMEM159, UNC13B, ZNF628, ZNF699 and LMNA) were found in the proband and his family members. ZRANB2. Functional expression was performed for the gene mutation and 3 Discussion [4-8] a pathogenic electrophysiological mechanism was uncovered . Many studies focus on the SCN 5A gene, which encodes the voltage-gated sodium channel type V alpha subunit and is Atrioventricular block (AVB) is mainly diagnosed according to located on 3p21-24. This gene plays an important role in rapid electrocardiogram findings and clinical manifestations include depolarization, conduction and maintenance of the cardiac symptoms such as palpitations, weariness, asthenia, dizziness action potential. Mutations in this gene can alter sodium and angina pectoris. Cerebral hypoperfusion as a result of AVB channel function and reduce sodium inflow current, slowing can cause symptoms including syncope and confusion. In severe action potential firing and reducing their peak amplitude in the cases heart failure and stroke can occur. The most effective depolarization phase. Therefore, excitability and conductibility treatment is permanent pacemaker implantation. AVB can be of myocardial cells are reduced, impairing cardiac conduction caused by a variety of factors with the most common being velocity [9]. myocardial inflammation resulting from rheumatic and viral DNA extraction from the patients in the family was performed myocarditis as well as other infections, vagal excitation, adverse for gene sequencing to detect mutant genes. No SCN5A mutant drug reactions, organic heart diseases, trauma and surgery. genes were found, suggesting that familial atrioventricular block These causes were excluded by the pedigree investigation. For might be caused by other gene mutations. Compared with the the 6 patients with this disease in the pedigree investigation, normal population, the patients in the family were found to have electrocardiograms suggested pre-excitation syndrome with 24 abnormal genes including KDELC2, SEC14L2, SEC31A, AVB. Initially, it was second-degree AVB that gradually DNAH9, EPB41L2, RFX8, KBTBD12, KLHL29, LRRC59, developed into third-degree AVB, constituting the family LRP5, MUC6, OLFML2B, PLXNA3, KCNH6, SALL1, pedigree of hereditary AVB. From the pedigree analysis, ARMCX4, SLC22A16, STON2, TTF1, TMEM159, UNC13B, hereditary transmission was continuous in the family with ZNF628, ZNF699 and ZRANB2. Although these genes have patients in 3 continuous generations. The patients in the family different sequences compared to the normal population, not were adult males, suggesting an incomplete autosomal dominant all are necessarily related to the onset of AVB and need further disease in the family. characterization by cytology experiments. Among these genes, Familial AVB is very rare clinically and occurs once patients KCNH6, a gene encoding a potassium channel, can potentially reach middle age. There is currently no treatment other than be related to the onset of the disease in the family. Its mutation pacemaker implantation to increase heart rate and this therapy can increase the resting membrane potential and threshold is generally recognized around the world [3], thus the quality value and decrease the excitability and conductibility of the of life for patients with this disease is greatly reduced. Defining atrioventricular node or bundle branch. the pathogenesis and causes of familial AVB plays a key role Currently, there are only a small number of reports on familial in prophylaxis and treatment. A total of 6 patients in the family AVB in China [10-12] and its genetic basis requires further research. presented with chest tightness and palpitations with syncope and Although most studies focus on SCN5A gene mutation, onset had heart rates of approximately 40 bpm before reaching the age of the disease in this family was unrelated to the SCN5A gene. of 40. Ambulatory electrocardiograms suggested bradycardia In recent years, molecular biological techniques combined with and AVB. In the family, I1, II2, II3, III2, III3 and III7 all the use of patch-clamp electrophysiology further elucidate the received permanent pacemaker implantation. IV1 and IV2 have role of mutations in familial AVB. Such studies can contribute no clinical manifestations of the disease. Electrocardiograms to the early diagnosis of high-risk populations with hereditary suggested pre-excitation syndrome, but no atrioventricular block, susceptibility, making it possible to formulate reasonable delayed interval or lost waves were found. These individuals measures of prevention and treatment. may require continued monitoring to determine if they indeed do Zhang et al III AVB block and gene detection References 1. congenital heart block, integration of clinical and research NKX2-5[J]. Science, 1998, 281(5373): 108-11 . Benson DW. 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