Mutational Screening By Whole Exome Sequencing in An Iranian Family With Alström Syndrome

Background and aim: alström syndrome (as) is a rare autosomal recessive multi-system ciliopathy disorder with cardinal features, including cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (dcm), and progressive hepatic and renal dysfunction. as has a suggested prevalence of 1/1000,000 in europe and north america. as is caused by bi-allelic mutations in the alms1 gene (2p13.1). its molecular function is presently unknown, although roles in ciliary function, intracellular transport, and cell cycle control have been proposed. the diagnosis of as can be a challenging task due to its rarity, its gradual appearance of cardinal symptoms and its similarity with other ciliopathy and genetic disorders, such as idiopathic cardiomyopathy, bardet-biedl syndrome (bbs), leber congenital amaurosis (lca) and some inherited mitochondrial dysfunctions. this study aimed to identify pathogenic mutations in a consanguine iranian family with as.methods: whole exome sequencing was performed on the genomic dna obtained from a 12 years old girl with as. then, for variant confirmation and segregation analysis, pcr-sanger sequencing was performed. we searched in the population databases (dbsnp, exac, 1000 genomes & genomad) and disease databases (clinvar & hgmd) to exclude the normal variations and investigate the novelty of the mutation. predicated pathogenicity of the candidate variant was investigated in silico by predictive algorithms.results: according to the bioinformatics analysis, computational modelling and segregation of variants, we identified two homozygous mutations close together in exon 8 of alms1 in the patient, including c.7262 g>t and c.7303-7305delag. the clinically normal parents were heterozygous for both mutations. these mutations have a very rare frequency and only reported in the heterozygous state in the public genomic databases.conclusion: finally, by using wes, we identified two homozygous mutations inherited in cis on each allele of alms1 in a child from a consanguineous marriage. we confirmed the pathogenicity of these variants through bioinformatics analysis, computational modeling and segregation in the pedigree. it should be reminded that wes is very useful in the accurate and early diagnosis of diseases with gradually emerging symptoms such as as, and this is very important for the effective clinical management of patients.