Abstract 11567: A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing
Background: Sitosterolemia is an extremely rare inherited disease characterized by increased levels of plant sterols such as sitosterol, the cause of which is ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene mutations. Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent self-limiting fever and serositis caused by mutations in FEMV gene. Molecular diagnosis for such cases through candidate-gene approaches have required a huge effort for a long time. Whole exome sequencing (WES) technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately ~30 % of success for diagnosing, and there is great interest in extending this approach to this rare phenotype.
Methods and Results: WES was performed for the proband (14 yr Japanese female, initial LDL cholesterol = 535 mg/dl) with histories of recurrent self-limiting episodes of fever and serositis. Among 206,430 variants found in the individual, we found 18,220 nonsense, missense, or splice site variants, of which 3,087 were rare (minor allele frequency ≤0.01 or not reported) in 1000 Genome (Asian population). Filtering assuming recessive pattern of inheritance successfully narrowed down the candidate to the compound heterozygous mutations in ABCG5 gene (c.1256C>T or p.Arg419His / c.1763-1T>G [splice acceptor site]) and MEFV gene (c.329 A>G or p.Leu110Pro / c.442G>C or p.Glu148Val). She was genetically diagnosed as a coincidence of sitosterolemia and FMF for the first time.
Conclusion: We report the first case exhibiting rare coincidence of sitosterolemia and FMF identified using WES. Such comprehensive approach is useful to identify causative mutations for multiple unrelated inherited diseases.
Author Disclosures: H. Tada: None. M. Kawashiri: None. A. Nohara: Research Grant; Modest; Aegerion, Astellas Pharma, AstraZeneca, Kowa, Shionogi, Takeda, Synageva BioPharma. Research Grant; Significant; Keiai-Kai Medical Corp., MSD, Sanofi. A. Inazu: None. H. Mabuchi: None. M. Yamagishi: None.
- © 2015 by American Heart Association, Inc.