Meta-analysis of genotype-phenotype associations in Alström syndrome

Introduction Alström syndrome (ALMS, #203800) is an ultra-rare monogenic recessive disease. This the syndrome is associated with mutations in the ALMS1 gene, which codes for a centrosome structural protein responsible for centrosome cohesion. The type of mutation associated with ALMS is mostly cLOF (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with little success. The difficulty in recruiting a large cohort in rare diseases is the main barrier to conducting this type of study. Methods In this study we have collected all cases published to date for ALMS. We have created a database with those patients who had a genetic diagnosis and an individualised clinical history. Finally, we have attempted to establish a genotype-phenotype correlation using the truncation site of the patient’s longest allele as a grouping criterion. Results We collected a total of 357 patients of which 227 had complete clinical information, complete genetic diagnosis and meta information regarding sex and age. We have seen that there are 5 variants in high frequency with p.(Arg2722Ter) being the most common variant with 28 alleles. There are no gender differences in disease progression. Finally, truncating mutations in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS. Conclusion The location of the mutation in the ALMS1 gene does not have a major impact on the phenotype developed by the patient. Only mutations in exon 10 of the ALMS1 gene were associated with a higher prevalence of liver disease.