Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients.

Brais Bea-Mascato,José M Millán,Diana Valverde,Carlos Solarat,Teresa Jaijo,Irene Perea-Romero,Fiona Blanco-Kelly,Carmen Ayuso

doi:10.3390/genes12020282

Abstract

Alström syndrome (ALMS) is an ultrarare disease with an estimated prevalence lower than 1 in 1,000,000. It is associated with disease-causing mutations in the Alström syndrome 1 (ALMS1) gene, which codifies for a structural protein of the basal body and centrosomes. The symptomatology involves nystagmus, type 2 diabetes mellitus (T2D), obesity, dilated cardiomyopathy (DCM), neurodegenerative disorders and multiorgan fibrosis. We refined the clinical and genetic diagnosis data of 12 patients from 11 families, all of them from Spain. We also studied the allelic frequency of the different variants present in this cohort and performed a haplotype analysis for the most prevalent allele. The genetic analysis revealed 2 novel homozygous variants located in the exon 8, p.(Glu929Ter) and p.(His1808GlufsTer20) in 2 unrelated patients. These 2 novel variants were classified as pathogenic after an in silico experiment (computer analysis). On the other hand, 2 alleles were detected at a high frequency in our cohort: p.(Tyr1714Ter) (25%) and p.(Ser3872TyrfsTer19) (16.7%). The segregation analysis showed that the pathogenic variant p.(Tyr1714Ter) in 3 families is linked to a rare missense polymorphism, p.(Asn1787Asp). In conclusion, 2 novel pathological mutations have been discovered in homozygosis, as well as a probable founder effect in 3 unrelated families.

Highlights

Alström Syndrome (ALMS; OMIM #203800) is an ultrarare recessive disorder, with an estimated prevalence lower than 1 in 1,000,000 in European-descent populations
1 is located in exon 5 [20], 7 are located in exon 8 [4,6,7], 1 in exon 9 [4], 1 in exon [19] and 1 in exon [4] of the Alström syndrome 1 (ALMS1) gene, and all of them lead to a stop codon
The analysis of the open reading frame (ORF) sequence showed the generation of a premature stop codon, resulting in a truncated protein in both cases

Summary

Introduction

Alström Syndrome (ALMS; OMIM #203800) is an ultrarare recessive disorder, with an estimated prevalence lower than 1 in 1,000,000 in European-descent populations. As in the case of other rare syndromes, consanguineous and/or geographically isolated populations have higher frequency values [1,2,3]. ALMS is a pleiotropic and multisystemic disorder characterized by a high inter- and intrafamilial variability, regarding the phenotype displayed, the age of onset and the severity of symptoms [4,5]. Other secondary features include seizures, hyporeflexia or multiorgan fibrosis that develops from adolescence onwards. This latter is very variable and can affect the liver, kidneys, lungs and gonads [8]. The remaining signs evolve slowly during childhood and adolescence, the most severe features can be detected before the first decade [4]

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