Clinical Research And Preliminary Analysis On Genetics Of Congenital Microtia With Thoracic Deformities

ObjectiveMicrotia is a common surface malformation in plastic surgery which presents various deformities of external ear as well as other organ systems.It not only seriously affects the patients’appearance and mental health,but also causes certain difficulties in its diagonosis and therapy.The aim of this study is to identify the characteristics and incidence of thoracic deformities in patients with microtia and to investigate the interaction between microtia and thoracic deformities.Through the whole genome exome sequencing of ten sporadic families which the children show microtia accompanied by thoracic deformities and bioinformatic analysis,to identify disease-causing genes and mutations and explore the possible pathogenic mechanism of these candidate genes.This study not only enhances our understanding of multisystematic deformity related to microtia,but provides novel insights into genetic research on microtia with thoracic deformities.And in the same time it broadens our mind to explore the molecular mechanism for microtia.Methods1.A total of 230 microtia patients in Plastic Surgery Hospital received a preoperative 3-dimensional chest computed tomography from November 2014 to September 2015.To investigate the incidences and characteristics of thoracic deformities,including rib deformities,rib cartilage deformities and spine deformities.Pearson X2 test and Spearman analysis were used to analyze the relationship between microtia and thoracic deformities.2.Ten sporadic patients with microtia and thoracic deformities were collected from August 2016 to December 2016.We performed the whole exome sequencing on ten patients and their parents.Bioinformatic analysis was used to identify candidate pathogenic variants.Results1.CT radiographs of 230 patients with microtia were reviewed,a total of 102(44.3%)patients were documented with thoracic deformities including 49 patients(21.3%)with rib deformities,75 patients(32.6%)with rib cartilage deformities and 8 patients(3.5%)with spine deformities.The incidence of rib deformities in microtia Ⅰ,Ⅱ,and Ⅲ was 3.8%.22.0%and 29.6%,respecti-vely.The incidence of rib cartilage deformities in microtia Ⅰ,Ⅱ,andⅢ was 11.5%.32.8%and 51.9%,respectively.The incidence of spine deformities in microtia I,Ⅱ,and III was 0.0%.2.3%and 14.8%,respectively.The patients with microtia III were found to have a higher incidence of rib,rib cartilage and spine deformities than those with microtia II,and patients with microtia Ⅱ were found to have a higher incidence of rib,rib cartilage and spine deformities than those with microtia I(P=0.034,P=0.007,P=0.002).2.Ten patients had no family history of congenital external ear malformation.They were all documented with thoracic deformities,including eight patients with the 12th rib deformities,one patient with the first and second rib deformities and one patient with the 12th rib deformities and rib cartilage deformities.3.After bioinformatic analysis of the whole exome sequencing data,we identified three candidate causal mutations.These are de novo missense variants:c.162C＞A,(p.54Y＞X)in PHF5A and c.424A>G(p.142I>V)in KIN,and compound heterozygous mutations c.476G>A(p.159R＞Q)and c.370G>A(p.124G＞S)in CYP26B1.The three mutations were predicted deleterious and highly conserved,hence,they may be related to the causes of patients.Conclusion1.The incidence of thoracic deformities was high in patients with microtia,and the incidence of thoracic deformities was correlated with the grade of microtia.The poorer one auricle developed,the higher the incidence of thoracic deformities was.2.Whole exome sequencing(WES)is an economic and efficient method.Through the preliminary genetic analysis,the three candidate causal variants:de novo mutations of PHF5A and KIN,compound heterozygous mutations of CYP26B1 may leads to the disease phenotype of the corresponding patients.