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. 2021 Feb 16;12(2):282.
doi: 10.3390/genes12020282.

Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients

Brais Bea-Mascato  1   2 , Carlos Solarat  1   2 , Irene Perea-Romero  3   4 , Teresa Jaijo  3   5 , Fiona Blanco-Kelly  3   4 , José M Millán  3   5 , Carmen Ayuso  3   4 , Diana Valverde  1   2
Affiliations

Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients

Brais Bea-Mascato et al. Genes (Basel). .

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.

Keywords: Alström syndrome; ciliopathies; founder effect; metabolic disease; novel mutations.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Pedigree chart and electropherogram for the patients carrying novel mutations. (A) Pedigree chart for family GBB-28, carrier of mutation c.2785C>T; p.(Glu929Ter) and electropherogram of the proband sequence compared to the control. (B) Pedigree chart for family UG-26225, carrier of mutation c.5420_5423del; p.(His1808GlufsTer20) and electropherogram of the proband sequence compared to the control.
Figure 2
Figure 2
Different relative allele frequencies for the pathogenic variants detected in the cohort, expressed as a fraction of total alleles (N = 24).
Figure 3
Figure 3
Single nucleotide polymorphism (SNP) segregation study in 3 families. (A) The mother´s genotype from family GBB-44, carrier of p.(Asn1787Asp) and p.(Tyr1714Ter) in heterozygosis. (B) The father´s genotype from the RP-1087 family, carrier of p.(Asn1787Asp) and p.(Tyr1714Ter) in heterozygosis. (C) The genotype of the GBB-46 proband with p.(Asn1787Asp) and p.(Tyr1714Ter) in homozygosis. *: p.(Asn1787Asp) (c.5359A>G; rs45608038).
See this image and copyright information in PMC

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