I am tring to identify a novel pathologic gene from a high myopia (near sight)
autosomal dominant family (four generations, 10 cases and 11 normal). Currently, we have mapped the pathologic gene in a 5.5M region on a chromosome through genome wide linkage analysis. Using next-generation sequencing technology (whole exome seq and whole genome seq), we do find a nonsynonymous SNV (on coding region of one gene) within the linked region co-segragate with disease phnotype in the family. It means all 10 high myopia patients are heterozygous of this mutation; while the normal individuals are wild-type. Geneticlly, such co-segragated nonsynonymous mutation is the pathologic gene of the family we are looking for. However, the mutation was found in general population (sample size: 250) with normal eye sight with frequecy of ~ 3%. In the sporadic high myopia cases (sample size: 60), the frequecy of this nonsynonymous mutation is also about 3%. In my opinion, it is impossible that the mutation is a causative factor with such high frequency.
Copy number varation was also tested (one high myopia boy and his normal father), no novel CNV were identified in the linked chromosome.
So, my question is:
a). The mutation can only be treated as a marker which is very close to the true pathologic mutation? If this is ture, how to perform further study to find the ture causative gene?
b). A very rare haplotye cause the disease and the mutation mentioned above is a member of the haplotype and other member is yet to identify ? If this is ture, how to perform further study?
or any other possibility I should think about?
Any idea how deal with such situation. Many many thanks for your help. U can also contact me by e-mail: fish_tang***@****