X-linked diseases are single gene disorders that are due to the presence of mutations in genes that reside on the X chromosome. X-linked recessive disorders are predicted from the family structure, where only boys are affected and there is no father to son transmission of the mutant allele. Heterozygous females are usually non-symptomatic carriers but can manifest a milder form of the disease. The identification of the genetic defect in X-linked disorders facilitates the diagnosis of affected individuals, aid in providing informative counseling and may help in prenatal diagnosis. Objectives: The study aims at mapping and identification of one gene responsible for congenital cataract and micropthalmia in a three-generation family.

We recruited 12 members of a family with a clear X-linked pattern of inheritance with three affected males, all showing congenital cataracts and microphthalmia. Gene mapping was attempted using a set of microsatellite markers selected to cover the whole X chromosome. Haplotypes were generated for all genotypes and the haplotypes were examined for alleles shared by the affected males and not shared by the unaffected males. Once the region of linkage was identified, we examined a few candidate genes by mutation analysis by resequencing in forward and reverse of one affected individual, one obligate carrier and one unrelated normal control. Candidate genes were chosen from the human genome public databases and were selected based on the possibility that they play a role in eye development or are expressed in fetal eyes.

The region of linkage is a 50 Mb in the pericentromeric region of the X chromosome (Xp21.1-q21.2). The candidate genes ARR3, DACH2 and BCOR were resequenced in forward and reverse, but no variations were detected.

We were capable of mapping the gene responsible for congenital cataracts and microphthalmia to the pericentromeric region of the X chromosome. We examined 3 candidate genes but no variations were detected. Currently, we are examining other candidate genes. If no mutant alleles are identified by this candidate gene approach, we will proceed by performing whole exome sequencing of the X chromosome (after enrichment) utilizing the next generation sequencing technology.


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