| [ Objective]A comprehensive analysis of the clinical characteristics and gene mutations of a family with familial amyloid multiple peripheral neuropathy.[Methods]1.Collection of clinical data of families: The clinical data of probands and family members were collected,and the clinical characteristics of the family were collected and analyzed.2.Gene Testing: We extracted the proband’s genomic DNA for whole exome sequencing.The TTR gene mutations found by whole exon sequencing were verified by Sanger sequencing in the proband and families.3.Bioinformatics analysis:(1)Ex AC＿EAS,Ex AC＿ALL,1000 Genomes and gnom AD databases were used for comparison;(2)db SNP,OMIM,HGMD and Clin Var databases were used to evaluate the pathogenic variation sites;(3)SIFT,Polyphen2,LRT,Mutation Taster and FATHMM protein function prediction software were used to predict the changes of protein function caused by gene variation.4.Pathogenicity analysis: Analysis of pathogenic variants was performed according to ACMG classification guidelines and the clinical phenotype of patients.[Results]1.Clinical manifestations: In this study,a family of 5 generations,a total of 21 people,4 of them are sick,including 3 males and 1 female(proband,maternal grandfather,eldest brother,mother).The clinical data of the proband,his eldest brother and his mother were collected.The clinical manifestations are that the age of onset is relatively late,the earliest onset after 55 years of age,with peripheral neuropathy as the first symptom,autonomic nervous function and heart damage are common,accompanied by visual impairment and central nervous system and systemic multiple organ damage.2.Auxiliary examination: Electrocardiogram showed different degrees of conduction block and sinoatrial node block of left and right ventricles;electromyography showed severe electrophysiological changes of peripheral nerve damage,mainly involving motor axons,sensory axons and myelin sheath;color Doppler ultrasound of the proband showed that the ventricular wall thickened obviously,the ventricular cavity became smaller,and the cardiac contractile force decreased significantly;sural neuropathy showed amyloidosis peripheral neuropathy.3.Gene detection: The base G of the second exon of TTR gene of the proband was replaced by base C,and the TTR protein showed an Arg54 Thr mutation,which was a heterozygous missense mutation,and the sanger sequencing of the blood samples of 7 family members showed that the proband,the eldest brother,the eldest daughter of the eldest brother and the second brother had the same site changes,while the father,the son of the eldest brother and the second brother’s daughter did not have the same site change.4.Bioinformatics analysis:(1)The missense mutation was not found in Ex AC＿EAS,Ex AC＿ALL,1000 Genomes and gnom AD databases,or the carrying rate was less than 5%.(2)The pathogenic mutation was evaluated by referring to the databases of db SNP,OMIM,HGMD and Clin Var.(3)The functional prediction software of SIFT,Polyphen2,LRT,Mutation Taster and FATHMM showed that the mutation led to the change of protein function.5.Pathogenicity analysis: According to the Classification criteria and guidelines of ACMG genetic variation,the variation accords with PS1+PS3+PM1+PM2+PP1＿Moderate+PP3.Comprehensive analysis of the pathogenic mutations in the family confirmed that the disease is an autosomal dominant familial amyloid peripheral neuropathy.[Conclusion]1.The family was diagnosed as familial amyloid polyneuropathy.The clinical feature of the family was that the onset age was relatively late,and it could occur in both men and women.The first symptom was peripheral neuropathy such as numbness,pain and fatigue in the extremities.Autonomic nervous function and heart damage are common,and may also be accompanied by visual impairment and central nervous system and systemic multiple organ damage.2.It was confirmed that the Arg54 Thr mutation of TTR gene was the pathogenic mutation of this pedigree,which was reported for the first time in China. |
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