Gene Mutation Analysis Of Ataxia Telangiectasia

Research backgroundAtaxia-telangiectasia(AT),also known as Louis-Bar syndrome,is a rare autosomal recessive disorder with an incidence of 1 / 100 000 ~ 1 / 40 000.The typical clinical manifestations of ataxia telangiectasia are progressive cerebellar ataxia in infants and young children,conjunctival and cutaneous telangiectasia,immunodeficiency,recurrent sinusitis and lung infection,ionizing radiation sensitivity and high incidence of tumors.In 1995,Shiloh Y determined that the ataxia-telangiectasia mutated gene(ATM gene)is the only cause of AT,and its encoded product is ATM protein.The mutation of ATM gene causes functional defects of ATM protein in cytoplasm.This leads to genomic instability,chromosome breakage and rearrangement,resulting in damage to many systems such as nerves,blood vessels,skin and endocrine,and neurological damage is particularly serious.Detection of mutations in the ATM gene is the gold standard for the diagnosis of AT.Ataxia telangiectasia is a progressive and progressive hereditary disease.Children with advanced disease die from infections and tumors,and the prognosis is poor.Ataxia telangiectasia causes great pain to families.The clinical manifestations of ataxia telangiectasia were summarized,and genetic mutation detection was conducted as early as possible for children with suspected AT in clinical practice,so as to achieve early detection,diagnosis and treatment.We provide genetic mutation analysis,genetic counseling and prenatal diagnosis to patients and their family members to reduce the incidence of such genetic diseases.ObjectiveTo summarize the clinical features and biochemical characteristics of 2 patients with ataxia telangiectasia in 2 families without any blood relationship.The gene sequencing method was used to study the molecular genetics and gene mutation types of patients with ataxia telangiectasia,and the correlation was inferred to provide genetic counseling and prenatal diagnosis for the patient's family.MethodsAfter reviewing the ethics committee of the First Affiliated Hospital of Zhengzhou University and obtaining informed consent from the family members of the family,the data of 2 probands and family members of 2 families with ataxia telangiectasia(clinical data,peripheral blood samples)were collected.In addition,20 blood samples from healthy children in the same outpatient clinic were collected as a control group.Extracting genomic DNA from peripheral blood samples using the Gene DNA Kit extraction kit.The second generation sequencing was used to detect the mutation of the whole exome gene.The detected mutation was compared with the original gene sequence in GeneBank,and then all the clinically significant mutation sites were verified by Sanger sequencing.Result1.In family 1,the second generation sequencing revealed a heterozygous mutation in the proband's ATM gene,which was:c.7627 delA on chr11:108202282 and c.8385-8394 del on chr11:108214065.The verification results of Sanger sequencing were consistent with the results of the second-generation sequencing.It was found that the proband's ATM gene had two heterozygous nucleotide variations:c.7627 delA on chr11:108202282 and c.8385-8394 del on chr11:108214065.The above two mutations were derived from the proband's father and mother,the father's ATM gene found c.7627 delA on chr11:108202282,and the maternal's ATM gene found c.8385-8394 del on chr11:108214065.2.In family 2,the second generation sequencing revealed a heterozygous mutation in the proband's ATM gene,which was: c.2638 delG on chr11:108138069 and c.2921+1G>C on chr11:108141874.The verification results of Sanger sequencing were consistent with the results of the second-generation sequencing.It was found that the proband's ATM gene had two heterozygous nucleotide variations:c.2638 delG on chr11:108138069 and c.2921+1G>C on chr11:108141874.The proband's mother ATM gene found a heterozygous mutation in c.2638 delG on chr11:108138069.The heterozygous mutation c.2921+1G>C may be inherited from the father or a new mutation.Conclusion1.The probands of the two families were conformde to the clinical symptoms,laboratory tests and gene mutation types of ataxia telangiectasia,and the clinical diagnosis was ataxia telangiectasia.2.The new mutations of c.7627 delA and c.8385-8394 del were found in family 1.The new mutations of c.2638 delG and c.2921+1G>C were found in family 2,and the pathogenicity of the above four new mutations was not reported in the literature.It has enriched the research on the level of molecular genetics of ataxia telangiectasia at home and abroad.