New Loci for Anterior Segment Dysgenesis on Chromosomes 10cen and 20p

Abstract

Purpose: : Seven families with recessive microcornea and polar cataract were ascertained in Northern Pakistan. Patients also have variable degrees of corneal clouding and iris coloboma. It is impossible to rule out microphthalmia as patients were examined in rural Pakistan, but eyes in these patients appear near normal in size and individuals are otherwise normal. These changes fall within the broad grouping anterior segment dysgenesis (ASD) but there are no exact matches for this phenotype/inheritance pattern in the literature. We therefore analysed the three largest families to determine whether the condition is new and whether it is genetically homogeneous.

Methods: : All family members underwent ophthalmic examination and DNA was extracted from blood. Consanguineous loops were present in all families. We therefore carried out SNP genotyping in three pedigrees and analysed the resultant data using IBDfinder software (available through autozygosity.org) to highlight homozygous regions. Loci were confirmed by microsatellite genotyping and linkage analysis.

Results: : Family MEP57 revealed a homozygous region in all affected individuals on chromosome 10. Microsatellites confirmed a linked region with a lod score of 3.02. However the genetic interval highlighted is large, extending from rs10508838 to D10S676, a 35mb interval containing many genes. Family MEP60 revealed a 6.3mb homozygous region on chromosome 20p, from rs473958 to rs1013214. Family MEP42 revealed a homozygous region at 22cen. The first two loci appear novel as no known anterior segment genes or disorders map to these region, but the third includes CRYBA4, mutations in which cause microphthalmia and cataract. None of the remaining families appear to map to these loci.

Conclusions: : These data point to new loci for ASD on chromosomes 10cen and 20p, and imply that this phenotype is highly genetically heterogeneous.

Keywords: anterior segment • genetics • linkage analysis