Analysis The Clinical And Mutation Characteristics Of An Ornithine Transcarbamylase Deficiency Family With A New Mutation Of OTC Gene

Background Ornithine transcarbamylase deficiency is a rare genetic disease caused by Ornithine transcarbamylase gene mutations.It is X-linked inheritance and is the most common type of urea cycle disorder.Ornithine Mutations in the OTC gene lead to a lack of OTC enzymes that affect the urea cycle,leading to hyperammonemia carbamoyltransferase deficiency.The disease mostly manifests as non-specific nervous system damage and liver damage,and is often misdiagnosed as a central nervous system infection and digestive system disease.Female heterozygotes have more diverse clinical manifestations due to non-random inactivation of the X chromosome.Repeated attacks can aggravate the nervous system damage,so early diagnosis,treatment and later intervention can reduce the patient’s nervous system damage and improve its prognosis.The current diagnosis of OTCD mainly relies on genetic testing,and mutations can occur in every position of the OTC gene.In this study,we analyzed the gene mutations and clinical characteristics of OTCD families accompanied by new mutations in the OTC gene.Objective To explore the clinical phenotype and gene mutation characteristics of OTCD families with new OTC gene mutations to enrich the OTC mutation gene library.Materials and methods1.Collect 1 pedigree suspected to be OTCD by the Department of Neurology of Henan Provincial People’s Hospital.Collect clinical data and peripheral blood samples of the proband and related family members,and draw a pedigree map.Full exon testing and Sanger single gene locus verification were performed on probands and related family members.2.As for the mutation site of the new gene,100 healthy people were selected to perform Sanger verification and control analysis.And the 1000 Genome database and HGMD database were consulted to compare the new mutation to determine whether it was a new mutation or a single nucleotide polymorphism.3.Use SIFT,Poly Phen2,Mutation-Taster and other software to evaluate the pathogenicity and evolutionary conservation of this variant.Using Swiss-Model to predict the tertiary structure of protein4.Perform analysis of X chromosome inactivation in the peripheral blood of the proband and her parents to determine whether the difference in phenotype between the proband and the mother is related to X chromosome inactivation.Results1.The proband has repeatedly experienced slow reactions,abnormal mental behaviors and gradual decline in intelligence after catching a cold.At the time of onset,blood ammonia 、 urine organic acid spectrum showed and uracil and orotic acid increased.Three of her sisters who died in childhood had similar symptoms.One elder brother and a pair of twin brothers died of breathing difficulties and convulsions during the neonatal period.There is a c.641A>C heterozygous missense mutation in exon 6 of the OTC gene of the proband and hermother,which causes the encoded amino acid at position 214 to be changed from histidine to proline(p.H214P).2.The mutation has not been reported.The software predicts that the mutation is a possible disease-causing mutation online,and the amino acid site of the mutation is in a highly conserved region by analyzing the conservative sequence of multiple species,and it is predicted that the high-level structure of the protein has changed.3.Both the proband and her mother have non-random inactivation of X chromosome.The proband’s paternal X chromosome is mainly inactivated,and the mother’s with a mutation of X chromosome is mainly inactivated.Conclusion1.Discover the new mutation site of OTC gene(c.641A>C p.H214P)enrichsthe OTC gene mutation database2.This mutation can cause severe clinical phenotypes in both neonatal males and heterozygous female patients.3.Analysis of X chromosome inactivation in peripheral blood may explain the difference in clinical manifestations of heterozygous female patients with the same mutation site and provide a basis for diagnosis.