Gene Mutation Analysis Of Tricho-rhino-phalangeal Syndrome

Background Tricho-rhino-phalangeal Syndrome(TRPS)is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene and characterized by craniofacial abnormalities and skeletal malformations.Clinical manifestations included sparse hair,unusual facial features,including absence of lateral eyebrows,few eyelashes,pear-shaped nose,long philtrum,thin upper lip,and small mandible.Skeletal deformities are generally short thumbs and great toes,and cone-shaped epiphyses of the fingers and toes.The disease can be divided into three types based on genetic and clinical manifestations.Type I has typical clinical manifestations.Type II is caused by the deletion of successive gene segments,including abnormalities in the TRPS1 gene and EXT1 gene,and in addition to the common clinical phenotype,includes mental retardation and multiple exogenic osteochondromas.Type III is the more severe manifestation of type I and includes more severe skeletal abnormalities,characterized by significant short stature and brachydactyly.When alopecia is the main manifestation,androgenetic alopecia should be differentiated,and gene sequencing should be used to confirm the diagnosis if necessary.Objective Panel targeted sequencing combined with sanger sequencing was used to detect the genes of related skin diseases in a patient with congenital alopecia and her parents.Dermoscopy and Reflection Confocal microscopy(RCM)were used to observe the characteristics of scalp hair loss.Scanning Electron Microscopy(SEM)was used to observe the hair characteristics and damage in the alopecia area of the patient.Understanding the relationship between the phenotype and gene mutations can help with the early diagnosis of the disease,as well as genetic counseling and prenatal diagnosis.Methods The clinical data and peripheral blood of a female patient with alopecia since infancy and her parents were collected,and the hair of the patient was collected.The morphology of the hair was observed under scanning electron microscope,and the scalp hair characteristics of the patient were observed under dermatoscopy and reflection confocal microscope(RCM).The mutation gene was analyzed by Panel targeted sequencing combined with Sanger sequencing.Results: The patient presented with thin,soft and sparse hair,bulbous nose,long philtrum,sparse lateral eyebrows,thin upper lip,and short hallux,but no deformity was observed in the fingers and toes.Dermoscopy and RCM showed sparse hair follicles and small hair diameter.Scanning electron microscopy showed that the damage of hair cuticle gradually increased from the root to the end,but no cavity or fracture was observed in the hair shaft.Panel targeted sequencing revealed a novel mutation in exon3 of the TRPS1 gene in the proband,c.378＿403del heterozygous mutation,which was a deletion at nucleotide positions 378-403 in the protein coding region.This mutation was a frameshift mutation,which would cause a frameshift in the peptide chain starting from amino acid 126.Sanger sequencing confirmed the same mutation site in the proband,which was not detected in his father and mother,suggesting that the mutation in the proband was a de novo mutation.According to the clinical manifestations and sanger sequencing analysis,tricho-rhino-phalangeal syndrome could be diagnosed.This mutation site was first reported in NCBI,HGMD,Clin Var and other databases.Conclusion:By panel targeted sequencing combined with sanger sequencing,we confirmed the diagnosis of a sporadic case of TRPS,and found new gene mutations,c.378＿403del: p.Phe126 leufs,which enriched the pathogenic gene mutation spectrum of TRPS1.This suggests that gene sequencing by targeted sequencing combined with sanger sequencing is an effective method for clinical diagnosis of congenital alopecia.The study of TRPS can provide a basis for early diagnosis and genetic counseling.