Identification Of A Causative Gene In A High Myopia Family

High myopia, also called pathological myopia, refers to the presence of a refractive error≤-6.00diopters (D), accompanied by the eye matrix change, which is one of the major causes of blindness. The inheritance mode of most familial high myopias is monogenic. So far many genes associated with familial high myopia have been reported, including ZNF644, SCO2, LEPREL1, LRPAP1, CCDC111and SLC39A5. Even though these genes can explain a small part of the patients with high myopia, the etiology for most patients is still unknown.Objective:Aim to identify causative gene of a high myopia family by genome-wide linkage analysis and exome sequencing.Methods:A four-generation pedigree with high myopia of Chinese Han population was recruited. Peripheral blood genomic DNA of19subjects in the family were extracted using conventional phenol chloroform method. Candidate interval were located by genome-wide linkage analysis. In order to get candidate variation, two patients and a normal subjects were selected to conduct exome sequencing. All the members in this family were sequenced to validate phenotype segregated with candidate variation by Sanger sequencing.500cases of control were included for Sanger sequencing. To identify whether or not there were other variants in the candidate gene, Sanger sequencing of all exons was carried out in an additional180sporadic high myopia patients.Results:4candidate intervals in chromosome2and6were located via genome-wide linkage analysis. Using exome sequencing, the missense mutations in2candidate genes were found in the chromosome2intervals located by linkage analysis. They are FER1L5:c.6235A>G (p.N2079D) and ANKRD39:c.479G>A(p.R160Q). Sanger sequencing showed the mutation of FER1L5didn’t segregate with myopia phenotype. The mutation of ANKRD39segregated with myopia phenotype. However, the mutation was not present in500controls. No mutations of ANKRD39were found in180additional probands with high myopia or sporadic patients.Conclusion:ANKRD39gene may be the causative gene of the high myopia family.