A Novel Locus For Congenital Simple Microphthalmia Families Mapping To 17p12-q12

Congenital microphthalmia (CMIC, OMIM 309700) is an ocular developmental malformation characterized by a small eye (2/3 of the normal volume), short axial length (less than 20 mm), high hyperopia, narrow palpebral fissure and small fossa orbitalis. The reported prevalence of microphthalmia at birth is 0.015% abroad and 0.012% in China. Most of the microphthalmia cases are sporadic, families with autosomal dominant, autosomal recessive and X-linked recessive inheritance were also reported. Previous studies demonstrated that microphthalmia was a genetically heterogeneous disorder. Several major causative genes and an increasing number of genetic loci linked to microphthalmos have been identified. Although the precise pathogenesis of microphthalmia is still unknown, it's considered that the formation of eyes may be associated with the mutations of involved in eye development at present.In our study, a five-generation congenital simple microphthalmia pedigree of Chinese origin in Qingdao of Shandong Province was collected. 28 blood samples including 15 male and 13 female (9 patients contained) were obtained from three generations of this family and all these individuals were analyzed. The disease in this family is inherited as autosomal-dominant pattern. Our previous research excluded 8 reported positions. In this study, a whole-genome scan and linkage analysis were performed in 19 individuals (9 patients contained). Maximal LOD score 3.86 at D17S1857 (θ=0) was obtained. Fine mapping was consequently carried out using microsatellite markers around this suspect locus for the whole families, a maximum two-point LOD score of 4.97(θ=0) at D17S1824 was obtained. The LOD scores for the microsatellite markers close to D17S1824 also strongly supported the linkage, and the highest LOD value reached to 4.91. Haplotype was then constructed and a novel locus for microphthalmia at chromosome 17pl2-ql2 was finally localized to a 20.78cM region between markers D17S799 and D17S1293.By candidate approach we searched for possible candidate genes related to eye development between D17S799 and D17S1293. Eight candidate genes were firstly screened for mutation in this family. However, no mutation was identified to be associated with disease. Mutation analysis in non-coding region of these eight genes and more candidate genes may help us to find out the molecular mechanisms of the disease in this family.