A genome-wide linkage scan in Tunisian families identifies a novel locus for non-syndromic posterior microphthalmia to chromosome 2q37.1.

Posterior microphthalmia (PM) is a relatively rare autosomal recessive condition with normal anterior segment and small posterior segment resulting in high hyperopia and retinal folding. It is an uncommon subtype of microphthalmia that has been mostly reported to coexist with several other ophthalmic conditions and to occur in sporadic cases. The membrane-type frizzled-related protein (MFRP) is the only gene so far reported implicated in autosomal recessive, non-syndromic and syndromic forms of PM. Here, we performed a clinical and genetic analysis using six consanguineous families ascertained from different regions of Tunisia and affected with non-syndromic PM that segregates as an autosomal recessive trait. To identify the disease-causing defect in these families, we first analysed MFRP gene, then some candidate genes (CHX10, OPA1, MITF, SOX2, CRYBB1-3 and CRYBA4) and loci (MCOP1, NNO1 and NNO2) previously implicated in different forms of microphthalmia. After exclusion of these genes and loci, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous pedigree. SNP genotyping revealed eight homozygous candidate regions on chromosomes 1, 2, 3, 6, 15, 17 and 21. Linkage analysis with additional microsatellite markers only retained the 2q37.1 region with a maximum LOD score of 8.85 obtained for D2S2344 at theta = 0.00. Further investigations are compatible for linkage of four more families to this region with a refined critical interval of 2.35 Mb. The screening of five candidate genes SAG, PDE6D, CHRND, CHRNG and IRK13 did not reveal any disease-causing mutation.