title: A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing.
abstract: Whole exome sequencing (WES) technologies have accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. We encountered a 13-year-old Japanese female initially diagnosed with familial hypercholesterolemia on the basis of clinical manifestations of severe hypercholesterolemia (initial LDL cholesterol=609 mg/dl at the age of one) and systemic intertriginous xanthomas with histories of recurrent self-limiting episodes of fever and arthritis. Both her phenotypes seemed to co-segregate in a recessive manner. We performed WES on this patient, who was considered a proband. Among 206,430 variants found in this 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 by assuming a recessive pattern of inheritance with the use of an in silico annotation prediction tool, we successfully narrowed down the candidates to the compound heterozygous mutations in the ABCG5 gene (c.1256G＞A or p.Arg419His/c.1763-1G＞A [splice acceptor site]) and to the double-compound heterozygous mutations in the MEFV gene (c.329T＞C/C or p.Leu110Pro/c.442G＞C/C or p.Glu148Val). The patient was genetically diagnosed with sitosterolemia and familial Mediterranean fever using WES for the first time. Such a comprehensive approach is useful for identifying causative mutations for multiple unrelated inheritable diseases.
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine.
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Okada
authors.forename: Saori
authors.initials: S
authors.lastname: Endo
authors.forename: Yuka
authors.initials: Y
authors.lastname: Toyoshima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Konno
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.forename: Akira
authors.initials: A
authors.lastname: Takao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5 / Q000235:genetics*; D000293:Adolescent; D008078:Cholesterol, LDL / Q000378:metabolism; D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000473:pathology; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000473:pathology; D007410:Intestinal Diseases / Q000235:genetics* / Q000473:pathology; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology; D008074:Lipoproteins / Q000235:genetics*; D010840:Phytosterols / Q000009:adverse effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C416945:ABCG5 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D008078:Cholesterol, LDL; D008074:Lipoproteins; D010840:Phytosterols