Gene Mutation Of Histone Modifying Enzyme And Human Disease

Background: The histone is the fundamental unit of nucleosome.Several posttranscriptional modifications occur in histone tails: acetylation,methylation,phosphorylation and ubiquitination.Histone modifications have important roles in transcriptional regulation,cell division,apoptosis,DNA repair,and DNA replication through altering chromatin architecture or recuiting other effective protein.Mutations in histone modifying enzymes lead to abnormal histone modification,which affects the biological effects mentioned above.They can lead to developmental abnormalities,mental retardation,behavior anomalies and even tumors.To date,acetylation and methylation modification of histones are the most studied,and nearly 100 kinds of catalytic enzymes have been found to be related to them.It has been reported that more than ten rare genetic diseases are associated with histone methyltransferases and acetyltransferases gene mutations.Because of its lack of highly unique clinical manifestations,it is hard to identify these diseases by clinical faeatures,such as growth abnormalities,specific body deformities and facial features.High-throughput sequencing technology greatly improves the possibility of accurate gene diagnosis for hereditary patients by virtue of its advantages of large-scale parallel and rapid detection.Through genomic gene detection,most of the important mutations carried by patients can be obtained,which makes it possible to accurately diagnose a series of pediatric clinical manifestations.Objective: The purpose of this study was to detect histone modifying enzyme gene mutations in rare diseases in China by proband exome sequencing and sequencing validation of core family members(trios),and to evaluate its clinical value in the diagnosis of rare genetic diseases.The phenotypic and molecular genetic characteristics of these diseases were analyzed to clarify the molecular etiology of their pathogenesis,and to improve the clinical understanding of the rare diseases.Methods: 1.Collect clinical data of patients with rare diseases;2.Collect DNA samples of patients and their family members,and conduct high-throughput sequencing for probands,including library establishment,hybridization,enrichment and capture,and sequencing on machine;3.Evaluate data quality according to parameters such as sequencing depth,and screen mutations by Ingenuity;4.Candidate gene mutations were validated by Sanger sequencing.Pathogenicity was assessed according to the guidelines of the American College of Medical Genetics and Genomics,and the data were further analyzed.Results: 1.Fifty-six patients with candidate gene mutations were detected after filtering and validation.KMT2 A and KMT2 D gene mutations were the most common.2.We reported 40 novel variants.The types of variation included missense,nonsense,frameshift,splicing sites,in-frame insertion/deletion and copy number variation.The pathogenic and likely pathogenic variants accounted for 66.07%(37/56)and 28.57%(16/56),respectively.3.We found 12 histone modifying enzyme gene mutations,which resulted in 10 related genetic diseases,mostly manifested as growth and development abnormalities and intellectual disorder.There was no significant correlation between genotype and phenotype of these diseases.The genetic heterogeneity is great.Conclusion: 1.This article studied the condition of rare diseases in China,and enriched the gene spectrum,mutation spectrum and phenotype spectrum of rare genetic diseases in Chinese population.2.Histone modifying enzyme gene mutation led to a group of neurodevelopment disorders with obvious genetic heterogeneity.Main clinic feature is growth and development disorders and intellectual deficits.Gene sequencing is effective on diagnosis of these rare diseases.