Purpose: Anophthalmia is a heterogeneous developmental disorder characterized by absent eyes whose diverse etiology encompasses chromosomal and monogenic aberrations, as well as environmental causes. Since the molecular basis has been defined in only a small proportion of cases and extending this offers potential to enhance understanding of key steps in ocular development, a consanguineous anophthalmic pedigree was investigated using homozygosity mapping.
Methods: DNA samples from six individuals, two anophthalmic, were genotyped with an array featuring approximately 620,000 single nucleotide polymorphisms (SNPs) in order to identify homozygous or copy number variant (CNV) regions. Candidate genes located in regions of identity by descent (IBD) defined by homozygosity mapping were subsequently screened by direct sequencing.
Results: Genotyping identified five homozygous intervals (4q26-28.1, 13q12.11, 14q22.1-22.2, 15q26.2-26.3 and 19q13.12) larger than 1 Mb that do not correspond with the known loci and which contain a total of 205 annotated genes. No CNVs were identified that segregated with the disease phenotype, and sequencing of five candidate genes (PRDM5, FGF2, SOS2, POU2F2 and CIC) did not identify any mutations.
Conclusions: Although constrained by the pedigree's size, the homozygosity mapping approach employed in this study extends the locus heterogeneity of anophthalmia. The results indicate that a novel molecular cause remains to be determined in this pedigree with the causative gene likely located within one of the five IBD regions.
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