A Molecular Genetic Investigation of Two Families With Macular Dysplasia in Association With Digit Abnormalities

Abstract

Purpose: : To present the clinical phenotype and molecular assessment of two families with a congenital syndrome of autosomal dominant macular dysplasia in association with digit abnormalities.

Methods: : Affected and unaffected members of two Caucasian non-consanguineous families were studied. Individuals underwent detailed clinical ophthalmic and systemic physical examinations. After informed consent, blood samples were taken for DNA extraction and genome-wide SNP genotyping using the Affymetrix GeneChip^® 250K microarray.

Results: : 6 female and 5 male affected individuals (age range 18 months - 69 years) were assessed. The macular defect was non-progressive and variable in severity from mild RPE loss with pigment deposition to excavated chorioretinal atrophic lesions. There was no evidence of global retinal dysfunction.7 affected patients displayed additional systemic abnormalities affecting their digits. These varied from clinodactyly (n=2) to either ectrodactyly (n=2) or brachydactyly (n=3) affecting the hands and feet.Whole genome SNP analysis was performed on both affected and unaffected individuals following the Affymetrix Sty microarray protocol. Genotyping data across 238000 SNP’s was analysed using both DM and BRLMM algorithms within the GTYPE 4.1 software platform.Known chromosomal loci for similar retinal phenotypes such as MCDR1 (6q14 - 6q16.2), MCDR3 (5p13.1 - 5p15.33) and MCDR4 (14q) were investigated and linkage was excluded, indicating that there are additional loci for developmental macular phenotypes.

Conclusions: : The molecular defect underlying this syndrome remains to be elucidated in the absence of linkage to known congenital macular dystrophy loci.

Keywords: genetics • gene microarray • retina