| ObjectiveMicrotia is a major surface malformation that can seriously affect the patients’appearance and mental health.It is of great significance to study the characteristics of microtia and related genetics.The aim of this study is to have a better understanding of the abnormality phenotypes that co-occur with microtia and analyze if there is a singnificant relationship between microtia and other deformities in Chinese population.Carrying out a detailed survey of family history to understand the genetic characteristics of patients with microtia.Using candidate genes mutation and copy number variation detecting in microtia patients to detect new varions and carrying out bioinformatics analysis.Through the above research,we will gradually deepen the cognition of microtia,which can be used as the basis for the research and prevention of molecular mechanism of microtia in the future.Methods1.A total of 672 patients with microtia were collected from December 2014 to February 2016 in the hospital-based study.All patients were examed in detail and classified into three types of microtia,with associated anomalies detected and recorded.The cases with associated anomalies were sub-classified according to the main organ system affected.Spss version 19.0 was used to verify the relationship between microtia and associated anomalies.And comparing with other countries’ associated anomalies data,to analyze the charateristics of the Chinese patients.2.Through the examination,we used direct inquiry and telephone follow-up method in the 672 patients above for obtaining and registering the information and family incidence of ear deformities.The main investigators were the probands,the first-degree relatives,the second-degree relatives,the third-degree relatives and the fourth-degree relatives.It was divided into familial group and sporadic group according to the background of the ear malformations of the patients’ relatives to explore the potential value.3.Randomly selecting 200 cases of patients with sporadic microtia.Mutation detection and copy number mutation detection of six candidate genes(HOXA1、HOXA2、EYA1、SIX1、SALL1、FGF3)were performed in the patients.The bioinformatic was used to analyze the variation.Results1.Showing preponderances of male(72%),unilateral(92.9%)and right-sided(63%),consistent with prior reports in the literature.We identfied that 293 patients(43.6%)were documented with one or more associated anomalies,especially the ear,face and neck,musculoskeletal,card-iovascular system were the most common associated anomalies.The poorer one auricle developed,the higher the incidence of associated anomalies.These studies exhibited noteworthy heterogeneity in the proportion of associated congenital anomalies,but was largely consistent with the weight of main organ system malformations.For example,generally the highest incidence of concurrent malformations was ear,face and neck system,followed by musculoskeletal system,cardiovascular system,followed by urogenital system,ranked behind were respiratory system,nervous system,digestive system.2.In this study,the proportion of the patients who had auricle deformity familial history was 34.1%,among which the proportion of first-degree relatives was the highest,and the proportion of second,third and fourth-degree relatives decreased,according with the laws of genetics.Parents of two-line background levels of patients with microtia constituted no significant difference in the ratio.There were 33.8%microtia patients associate with tags/fistula,and these patients had a higher incidence of familial history than the patients without tags/fistula.3.In one of the 200 patients,a missense mutation(c.260C>T,p.A87V)of the HOXA2 gene was identified.The mutation was not present in the parents,and the mutation was not found in 1000 human genome,HGMD,the ESP6500,dbSNP,ExAC database.Bioinformatics analysis of the mutation was highly conserved,and presumably pathogenic.Two copies of the EYA1 gene were found to be deletion presumed to be pathogenic.Conclusion1.This was the first detailed and specific study of associated anomalies with microtia in Chinese patients.The incidence of associated deformities was high in patients with microtia,and existing great clinical heterogeneity among them.We should pay more attention to investigate associated congenital anomalies for future studies exploring the etiology of microtia and provide better treatment for patients.2.In this study,the occurrence of familial history of ear malformations was 34.1%,and there were genetic characteristics of vertical transmission,generation inheritance and family aggregation.Other ear deformities in relatives should not be overlooked when studying the genetic characteristics of microtia.Although the current pathogenesis of microtia was unknown,but genetic factors can not be ignored.3.In this study,200 patients carried out candidate genes mutation and copy number variation detecting,and successfully identified the HOXA2 c.260C>T(p.A87V)mutation.in the coding region of a unilateral sporadic patient.Differenced with previous studies in the family cases,this mutation was located in exonl.Our data expanded the spectrum of HOXA2 mutations.And the deletion of EYA1 gene copy number were detected in two patients.These findings may be the causative factors,although not clear the specific mechanism,experimental verification was necessary. |
PDF Full Text Request