The number of genes identified to be responsible for autosomal dominant genetic conditions far exceeds those identified for autosomal recessive conditions. This is expected because autosomal recessive disorders are rare and a single large family or a large number of smaller families are needed for gene mapping and identification. However, this hurdle can be overcome by homozygosity mapping utilizing inbred families.

The aim of this study is to map loci and identify genes that play a role in autosomal recessive disorders among Arab families and to examine their role with the final aim of outlining novel genes and pathways. The investigation capitalizes on utilizing large inbred families, as well as smaller inbred families, by employing homozygosity approaches for mapping the etiologic genes.

It includes the recruitment of families and obtaining detailed clinical, genealogical and genotypic data. Families with pedigrees that provide suggestive evidence of autosomal recessive mode of inheritance and with consanguinity are selected. Homozygosity mapping is done by genome wide SNP genotyping using dense chips, followed by linkage analysis.

We performed homozygosity mapping on one recruited family to seek a region of homozygosity shared by affected individuals. This family includes eight individuals from 4 related sibships in an extended Palestinian family who suffer from congenital cataract. Homozygosity mapping revealed a region flanked by rs4276160 (3p22.1) and rs749512 (3p21.31) on the short arm of chromosme 3. This interval contains 92 genes, none of which has been implicated in eye disease. Further investigation for this family is currently underway using whole exome sequencing to identify the causative gene mutation. Other examples will be presented.

Homozygosity mapping utilizing inbred families is a very powerful tool for gene mapping in autosomal recessive families. However, the region of linkage is usually big and contains a large number of genes, which is prohibitive with the classic technology. Genomic approaches such as whole exome sequencing is yet another powerful tool to overcome this hurdle.


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