Identification of disease-causing genes in inherited metabolic diseases by SNP microarray method

Inherited metabolic diseases are single gene disorders resulting from defects in the synthesis or degradation pathways of proteins, carbohydrates and fatty acids. In this study, it was aimed to find the genetic loci responsible for these diseases and identifying the disease causing mutations in candidate genes in this loci through genome-wide genotyping and homozygosity mapping analysis in six families with undiagnosed metabolic /neurometabolic disease by detailed clinical and laboratory studies showing genetic disease with autosomal recessive mode of inheritance. Affymetrix 250K SNP microarray, which is an effective method for genome-wide genotyping was used in the study; as a result of haplotype analyzes in the families based on autosomal recessive inheritance model, C19orf70, CLN8, COA7, HIKESHI, MAG and SNX14 genes were identified as candidate genes responsible for metabolic/neurometabolic diseases. All exons of identified candidate genes were screened for mutations by automated DNA sequencing method. The mutation analysis revealed three previously identified mutations: c.1108+1181_2108-2342del in the SNX14 gene, IVS3-2A>G in the C19orf70 gene, c.160G>C;p.Val54Leu in the HIKESHI gene and novel c.221G>A;p.Gly74Asp mutation in CLN8 gene. The families included in the study were undiagnosed patients, who were examined with detailed interdisciplinary study for known metabolic/neurometabolic diseases by conventional methods (metabolite screening, enzyme analysis, radiological examinations or single gene mutation screening). In this study, genetic locus and disease causing genes in these families were successfully identified using high-throughout SNP chips. The homozygosity mapping approach was used very efficiently to find genes responsible for diseases, especially in nuclear families with one or two affected children. Keywords: Homozygosity mapping, inherited metabolic disease, microarray, SNP