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Case Reports
. 2020 Sep 1;21(1):173.
doi: 10.1186/s12881-020-01110-1.

A very early diagnosis of Alstrӧm syndrome by next generation sequencing

Leonardo Gatticchi  1 , Jan Miertus  2   3 , Paolo Enrico Maltese  4 , Simone Bressan  3 , Luca De Antoni  5 , Ludmila Podracká  6 , Lucia Piteková  6 , Vanda Rísová  7 , Mari Mällo  8 , Kaie Jaakson  8 , Kairit Joost  8 , Leonardo Colombo  9 , Matteo Bertelli  3   5
Affiliations
Case Reports

A very early diagnosis of Alstrӧm syndrome by next generation sequencing

Leonardo Gatticchi et al. BMC Med Genet. .

Abstract

Background: Alström syndrome is a rare recessively inherited disorder caused by variants in the ALMS1 gene. It is characterized by multiple organ dysfunction, including cone-rod retinal dystrophy, dilated cardiomyopathy, hearing loss, obesity, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus and systemic fibrosis. Heterogeneity and age-dependent development of clinical manifestations make it difficult to obtain a clear diagnosis, especially in pediatric patients.

Case presentation: Here we report the case of a girl with Alström syndrome. Genetic examination was proposed at age 22 months when suspected macular degeneration was the only major finding. Next generation sequencing of a panel of genes linked to eye-related pathologies revealed two compound heterozygous variants in the ALMS1 gene. Frameshift variants c.1196_1202del, p.(Thr399Lysfs*11), rs761292021 and c.11310_11313del, (p.Glu3771Trpfs*18), rs747272625 were detected in exons 5 and 16, respectively. Both variants cause frameshifts and generation of a premature stop-codon that probably leads to mRNA nonsense-mediated decay. Validation and segregation of ALMS1 variants were confirmed by Sanger sequencing.

Conclusions: Genetic testing makes it possible, even in childhood, to increase the number of correct diagnoses of patients who have ambiguous phenotypes caused by rare genetic variants. The development of high-throughput sequencing technologies offers an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.

Keywords: ALMS1; Alström syndrome; Case report; Next generation sequencing.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Sequence chromatograms of the variants identified in the proband. The chromatograms show the c.1196_1202del: p.(Thr399Lysfs*11) (upper panel) and the c.11310_11313del: p.(Glu3771Trpfs*18) (lower panel) heterozygous deletions. The family pedigree shows the compound heterozygous state of these two variants in the proband
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