Coppola, Antonietta (2011) IDENTIFICATION OF DISEASE GENES FOR RARE AUTOSOMAL RECESSIVE EPILEPTIC SYNDROMES BY HOMOZYGOSITY MAPPING. [Tesi di dottorato] (Unpublished)

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Introduction: The genetics of the most common neurological disorders, including epilepsy, with mendelian inheritance has been dissected in the last twenty years. However the genetic etiology of some rare epileptic conditions is still unknown. This research project focuses on rare autosomal recessive (AR) epileptic conditions. The genetic data obtained so far indicate that about half of cases affected by autosomal recessive disorders carry a homozygous mutation descending from a unique ancestor (founder effect). The putative mutation is contained within a segment of the DNA, called “identical by descent” (IBD), that is transmitted along the generations. This segment is characterized by a set of contiguous homozygous polymorphisms (SNP) and may be detected using a genome wide genotyping approach, namely the “homozygosity mapping” which allows the typing of a great number of SNP in order to detect very small IBD segments. Thus nuclear families (sib-pairs) originating from restricted areas can be genotyped in order to identify a new AR disease genes. In addition the novel sequencing methods can further follow up these regions allowing the rapid screening of hundreds genes. Material and methods: Families with at least two affected siblings affected by a rare epileptic condition sharing the same clinical pictures have been selected. Parental ancestors should have originated from the same geographical area. The affected relatives, their parents and unaffected siblings have been genotyped using the Axiom Genome wide human assay (Affymetrix). A classical linkage analysis has been performed in case of a negative result from the homozygosity mapping approach for families with more than two affected relatives. Homozygosity regions have been then analyzed using a classical Sanger sequencing or using a next generation sequencing approach. Results and discussion: homozygosity mapping allowed the identification of homozygosity stretches in one out of four families. Combined analysis (homozygosity mapping plus linkage) allowed the identification of narrow homozygosity areas in two families. The analysis of the genes included in the isolated stretches is ongoing. The negative result in family 3 and the eventuality of a negative result for the ongoing sequencing analysis can be explained hypothesizing a different inheritance pattern (X-linked, low penetrance heterozygosity, non mendelian and digenic inheritance, compound heterozygousity) or methodology limiting issue (mutation contained in a segment shorter than the homozygosity mapping cut off).

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