A de novo mutation of the LDL receptor gene as the cause of familial hypercholesterolemia identified using whole exome sequencing.

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.