title: A de novo mutation of the LDL receptor gene as the cause of familial hypercholesterolemia identified using whole exome sequencing.
abstract: We report a rare case of heterozygous familial hypercholesterolemia (FH) caused by a de novo mutation in LDL receptor (LDLR) gene identified using whole exome sequencing. An 11-year-old female without any family histories of hypercholesterolemia was referred to our hospital to make clinical as well as molecular diagnoses. She was first diagnosed as hypercholesterolemia at the age of 3 (initial total cholesterol=381mg/dl) without any secondary causes. Because of her lipid profile, heterozygous FH was initially suspected, however; the lipid levels of her parents were normal. Accordingly, she was suspected as a recessive form of hypercholesterolemia, such as sitosterolemia or autosomal recessive hypercholesterolemia. Whole exome sequencing was performed on 4 individuals, including the proband, her parents, and her unaffected younger sister. The initial analysis assuming a recessive inheritance was unsuccessful, leaving a few candidate genes without any evidence supporting cholesterol metabolism. However, we found only one de novo mutation in LDLR gene across her whole exome region, assuming de novo mutation occurrence (c.1136G>A or p.Cys379Tyr). This mutation has already been reported to cause FH, including Japanese, and finally, she was diagnosed as heterozygous FH caused by a de novo mutation in LDLR gene. Comprehensive genetic analysis is quite useful to make a correct diagnosis in such cases.
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan. Electronic address: ht240z@sa3.so-net.ne.jp.
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.affiliation: Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hosomichi
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Okada
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Kawashiri
authors.affiliation: Department of Advanced Research in Community Medicine, Kanazawa University, Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.affiliation: Department of Laboratory Science, Molecular Biochemistry and Molecular Biology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.affiliation: Hamajiri Clinic, Takasaki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tomizawa
authors.affiliation: Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Advanced Research in Community Medicine, Kanazawa University, Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D011973:Receptors, LDL
keywords: Familial hypercholesterolemia; LDL cholesterol; LDLR; Whole exome sequencing; de novo mutation