The Study On The Relationship Of HOXA1Gene Mutations And The Congenital Heart Disease

Congenital heart disease （CHD） is one of the most common human birth defects. Over the last few decades, a variety of CHD-causing gene mutations have been identified. HOXA1gene is one of the earliest and most anteriorly expressed Hox genes, which play a fundamental role in embryonic morphogenesis. The recent studies in humans and mice indicated that HOXA1has a previously unrecognized role in development of the cardiovascular system. However, there have been no report adout HOXA1in CHD patients until now. The aim of this study was to identify potential pathological mutations in the HOXA1gene in340Chinese children with ventricular septal defect and168families with complex CHD respectively to gain insight into the etiology of CHD.Objective:The aim of this study was to identify potential pathological mutations in the HOXA1gene in Chinese children with ventricular septal defect （VSD） and to gain insight into the etiology of CHD.Methods:A total of340VSD patients and200normal subjects were studied. Two exons and nearby introns corresponding to the human HOXA1gene were amplified by polymerase chain reaction （PCR）. The PCR products were purified and directly sequenced.Results:We did not reveal any non-synonymous mutation in the coding regions in the HOXA1gene. Two novel synonymous mutations （c.C210T p.His70His; C.T861A p.Arg287Arg） were detected. These mutations were not observed in200controls.Two kinds of previously reported histidine repeat deletions variants （c.211₂13delCAC, p. H71del; c.205₂13delCACCACCAC, p.H69_H71del）were identified in both normal and VSD patients.Conclusions:This study is the first attempt to investigate the possible role of the HOX41gene in VSD. Although our results did not show any pathogenic HOXA1mutation, our results suggest that VSD might not be a clinically isolated manifestation of HOXA1mutations. Objective:The purpose of this study was to identify potential pathological mutations in the HOXA1gene in Chinese family with complex CHD and to investigate the role of HOXA1in the CHD.Methods:A total of168families with complex CHD and200normal subjects were studied. Two exons and nearby introns corresponding to the human HOXA1gene were amplified by polymerase chain reaction （PCR）. The PCR products were purified and directly sequenced.Results:A homozygous deletion mutation of c.205₂13del in exon1of the HOXA1gene was identified in an eight-month-old female infant with complete atrioventricular septal defect （AVSD）. Ultrasonic echocardiogram of the affected infant revealed obvious deletion of the inferior part of atrial septum, the superior part of ventricular septum, and the muscular part of ventricular septum. This homozygous mutation was not identified in100controls, and was predicted to lead to three histidines deletation of the HOXA1protein. This affected individual is offspring of consanguineous marriages. We analyzed genomic DNA of her phenotypically normal parents and found this mutation were heterozygous. We also detected two single and multiple histidine insertions variants in CHD patients and normal subjects （c.211₂13insCAC, p.H71ins; c.205₂13insCACCACCAC, p.H69_H71ins）, one of them was novel. Two kinds of previously reported histidine repeat deletions variants were identified in both normal and CHD individuals in this part.Conclusions:The novel homozygous polyhistidine deletion mutation may be the pathogenic HOXA1mutation of complex CHD. HOXA1mutations are a rare cause of isolated complex CHD and mutational analysis is not recommended for sporadic CHD cases born to unrelated parents. The further studies are necessary to substantiate the functional significance of polyhistidine sequence in HOXA1.