Özet:
Identification of disease genes has a key importance in understanding the molecular mechanisms of disease pathogenesis as well as in expanding our knowledge on gene function. Linkage mapping is a powerful method to identify the regions in the genome that possibly harbor the gene responsible for the disease in a family. Once the disease locus is identified, the genes within that locus are searched for variants that could be associated with the disease. Advances in sequencing technologies in the last decade made mutation search much easier; causative mutations underlying the disease can be identified via whole exome sequencing even in small families. In this study, causative genes for five inherited disorders were identified. In a large consanguineous family with four members afflicted with Cone-Rod Dystrophy (CORD), we identified a homozygous mutation p.R106P in novel disease gene POC1B, encoding a centriolar protein. We identified homozygous missense mutation p.Q21P in CEP290, encoding another centriolar protein, in four patients afflicted with Optic Atrophy (OPA) in a large inbred family. In three of those patients, we additionally detected a novel and homozygous variant in ACSS3 possibly underlying the extraocular neurological symptoms shared by at least two of the patients. For the other three diseases we studied, identified mutations were all homozygous and truncating: ALDH1B1 p.G388EfsX23 for Amyotrophic Lateral Sclerosis (ALS), P2RX6 p.K331EfsX26 for Rett syndrome and NALCN p.Q642X for Infantile Neuroaxonal Dystrophy. Further, one difficulty in studying large families is demonstrated in OPA family, in which two genes are responsible for the variable phenotype. Our findings expand the spectrums of phenotypes of CORD, OPA, ALS, RTT, and INAD, for which we identified novel causative genes, and shed light onto the functions of the causative, novel genes. Screening identified genes for mutations could benefit families afflicted with diseases with similar manifestations as in our respective study families.
