Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients

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.

A novel missense ALMS1 variant causes aberrant splicing identified in a cohort of patients with Alström syndrome

“…Consistent with previous reports ( Marshall et al, 2005 ; Marshall et al, 2007a ; Marshall et al, 2007b ; Marshall et al, 2015 ; Ozantürk et al, 2015 ; Bea-Mascato et al, 2021 ), most of the variants (85%, 28/33) detected in the current cohort were clustered in exons 8, 10, and 16, further confirming these three exons as ALMS1 variant hot spots. The exons 8,10 and 16 are the three largest exons of the ALMS1 gene, containing 6.1 kilobases (kb), 1.9 kb and 1.2kb, respectively.…”

“…All the patients in this study suffered from ocular symptoms, while the systemic manifestations in our cohort were highly variable. The frequencies of other systemic symptoms were comparable to those reported in previous studies, except for DCM ( Marshall et al, 2005 ; Marshall et al, 2007a ; Marshall et al, 2007b ; Marshall et al, 2015 ; Ozantürk et al, 2015 ; Bea-Mascato et al, 2021 ), which was not observed in our cohort of patients. In one previously reported Chinese cohort that included 21 patients, DCM was observed in 17% of the patients ( Rethanavelu et al, 2020 ).…”

“…The exons 8,10 and 16 are the three largest exons of the ALMS1 gene, containing 6.1 kilobases (kb), 1.9 kb and 1.2kb, respectively. These three exons occupy 74% (9.2kb/12.5 kb) of the whole coding region, which, in part, makes them the hotspots ( Bea-Mascato et al, 2021 ). All the variants were either truncating variants (non-sense and frameshift indels) or large deletions involving one or several exons.…”

“…At present, 387 ALMS1 variants have been recorded according to the Human Gene Variant Database (HGMD) Professional 2021.4. Most variants are located in exons 8, 10, and 16, making these locations variant hotspots ( Marshall et al, 2007b ; Marshall et al, 2015 ; Ozantürk et al, 2015 ; Bea-Mascato et al, 2021 ). The majority of the ALMS1 variants are truncating variants, such as non-sense and frameshift indels, and they introduce a premature termination codon (PTC), causing premature protein truncation and triggering a non-sense-mediated decay (NMD) process ( Marshall et al, 2005 ; Marshall et al, 2007a ; Marshall et al, 2007b ; Marshall et al, 2011 ; Marshall et al, 2015 ; Ozantürk et al, 2015 ; Bea-Mascato et al, 2021 ).…”

“…Most variants are located in exons 8, 10, and 16, making these locations variant hotspots ( Marshall et al, 2007b ; Marshall et al, 2015 ; Ozantürk et al, 2015 ; Bea-Mascato et al, 2021 ). The majority of the ALMS1 variants are truncating variants, such as non-sense and frameshift indels, and they introduce a premature termination codon (PTC), causing premature protein truncation and triggering a non-sense-mediated decay (NMD) process ( Marshall et al, 2005 ; Marshall et al, 2007a ; Marshall et al, 2007b ; Marshall et al, 2011 ; Marshall et al, 2015 ; Ozantürk et al, 2015 ; Bea-Mascato et al, 2021 ). By contrast, only 19 missense variants have been recorded, but their pathogenicity remains unclear ( Marshall et al, 2007b ; Marshall et al, 2015 ).…”