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Dr. William B. Rizzo, MD
Background: Sjögren-Larsson Syndrome (SLS) is a rare autosomal recessive disease characterized by ichthyosis, neurological retardation, spastic diplegia and a distinctive retinopathy. It is caused by bi-allelic mutations in the ALDH3A2 gene, which result in decreased activity of fatty aldehyde dehydrogenase (FALDH). Although known to be a rare disease, the incidence of SLS is not established. We therefore used a bioinformatics approach to determine the incidence of SLS.
Methods: To estimate the incidence of SLS, we used mutation prediction programs PROVEAN, SIFT, and PolyPhen-2 to identify potential disease-causing DNA variants in the ExAC and NHLBI databases of >70,000 individual exomes. Missense variants were produced in a ALDH3A2 cDNA mammalian expression vector using site-directed mutagenesis, transfected into CHO cells, and FALDH activity was measured to determine residual enzyme activity.
Results: In the ExAC and NHLBI exome databases, we identified 696 ALDH3A2 variants consisting of missense (295), insertions/deletions/frameshifts (28), nonsense (7), intronic/splice-site (319) and others (47). Among SLS patients, 124 pathogenic ALDH3A2 variants have been reported; of the 55 missense variants, 40 were correctly predicted to be pathogenic by all 3 mutation analysis programs, indicating only 73% accuracy. Among the ALDH3A2 variants in the exome databases, we selected 23 missense variants predicted by all 3 software programs to be pathogenic for expression in mammalian cells and measured FALDH enzyme activity. Only 10/23 missense variants coded for an enzyme that had
Conclusions: Based on the US population (330 million) and normal life expectancy of SLS, we estimate that 733-1,031 SLS patients reside in the US, indicating that SLS is an ultra-rare disease.
SLS, FALDH, ALDH3A2, bioinformatics, estimating incidence
Kassing, Emily; Siefker, Edward; and Rizzo, William B., "Estimated Incidence of Sjögren-Larsson Syndrome Using Bioinformatics Databases and Software Prediction Programs" (2021). Posters: 2021 Summer Undergraduate Research Program. 44.