Özet:
Disease gene identification is an important area in genetics. Consanguineous marriages are very common in some populations and lead to emergence of rare diseases. To uncover the functions of our genes and the molecular bases of diseases, novel disease genes need to be identified. Later the effect of the mutation on the protein could be investigated by various analyses. Also, discovery of a new disease gene can be a glimmer of hope for the patients who are hoping for definite diagnosis and development of therapies. The steps of the disease gene identification is mapping the locus by linkage analysis or homozygosity mapping, identifying the causative mutation by exome sequence analysis and relating the mutation to the disease pathology, thus uncovering the molecular pathogenesis. Possible or known effect of the mutation can be investigated via computational algorithms and in the light of the information in published studies and databases. In this thesis study, causative genes were searched in eight consanguineous families afflicted with six different recessive diseases. The two identified genes and the identified mutations are PDIA3 (p.Cys57Tyr) in Syndromic Intellectual Disability family and CEP19 (p.Tyr65*) in Bardet-Biedl Syndrome family. Besides, in BBS family possible modifiers GLI1 p.Gly274Arg, CCDC28B p.Phe110Phe, MKKS/BBS6 p.Ile339Val, C8ORF37 p.Ala178Val and TMEM67 p.Asp799Asp were identified/detected. In Isolated Intellectual Disability family, missense PTRHD1 p.Cys52Tyr mutation confirmed that the gene is responsible for ID. Gene expression assay revealed wide expression in brain. In Intellectual Disability and Hypothyroidism family missense TPO p.Asp240Gly was identified. Intronic splicing c.6375-1G>C in SPTBN2 in Spinocerebellar Ataxia family unraveled the basis of dominant vs recessive effects of the variants in this gene. Synonymous p.Ile382Ile in TNKS2 in one of the Pleuroparenchymal Fibroelastosis families was identified as the strongest candidate. No candidate variant could be identified in the other two families, indicating genetic heterogeneity for this disease.
