Genotype-phenotype associations in Alström syndrome: a systematic review and meta-analysis

Abstract

Background: Alström syndrome (ALMS; #203800) is an ultrarare monogenic recessive disease. This syndrome is associated with variants in the ALMS1 gene, which encodes a centrosome-associated protein involved in the regulation of several ciliary and extraciliary processes, such as centrosome cohesion, apoptosis, cell cycle control and receptor trafficking. The type of variant associated with ALMS is mostly complete loss-of-function variants (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 limited 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 collected all cases of ALMS published to date. We created a database of patients who had a genetic diagnosis and an individualised clinical history. Lastly, we attempted to establish a genotype-phenotype correlation using the truncation site of the patient's longest allele as a grouping criteria.

Results: We collected a total of 357 patients, of whom 227 had complete clinical information, complete genetic diagnosis and meta-information on sex and age. We have seen that there are five variants with high frequency, with p.(Arg2722Ter) being the most common variant, with 28 alleles. No gender differences in disease progression were detected. Finally, truncating variants in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS.

Conclusion: Pathogenic variants in exon 10 of the ALMS1 gene were associated with a higher prevalence of liver disease. However, the location of the variant in the ALMS1 gene does not have a major impact on the phenotype developed by the patient.

Keywords: ALMS, Alström's syndrome; Meta-analysis; ciliopathy; genotype-phenotype; metabolic disease; obesity; rare disease; retinal disease.

Figure 1

Cohort description of 227 patients with Alström syndrome (ALMS). (A) Counting of the different alleles in the cohort. Alleles with more than two copies in the cohort are represented. (B) Number of alleles per exon in the study cohort. (C) Patients grouped by their allele of the ALMS1 gene with the furthest truncation variant. (D) Age composition in the subgroups with the longest allele of the ALMS1 gene truncated before exon 9 (group 1, G1), between exon 9 and exon 14 (group 2, G2), and after exon 14 (group 3, G3).

Figure 2

Phenotypic impact of different subgroups of patients with ALMS. (A) Prevalence of the five main syndromic groups in the cohort: vision impairments (VI), metabolic anomalies (MT), hearing anomalies (HL), heart anomalies (HRT) and liver anomalies (LIV). (B) Distribution of syndromic scores calculated from the presence or absence of the five most relevant syndromic groups. (C) Gender comparison of syndromic scores. (D) Comparison of the syndromic scores between age groups. (E) Comparison of the syndromic scores between subgroups created from the longest allele of the ALMS1 gene. ALMS, Alström syndrome; F, female; G1, group 1; G2, group 2; G3, group 3; M, male.

Figure 3

Correlation study between the prevalence of symptoms and the truncation site of the ALMS1 gene. (A) Evolution of the syndromic score among the subgroups by the longest allele of the ALMS1 gene in the different age groups. (B) Prevalence of the different symptom clusters in the subgroups by the longest allele of the ALMS1 gene. G1, group 1; G2, group 2; G3, group 3; HL, hearing anomalies; HRT, heart anomalies; LIV, liver anomalies; MEND, mental anomalies; MT, metabolic anomalies; PUL, pulmonary anomalies; REN, renal anomalies; REP, reproductive system anomalies; VI, vision impairments.