A Japanese case of familial hypercholesterolemia with a novel mutation in the LDLR gene

摘要

Introduction Familial hypercholesterolemia (FH, OMIM number #143890) is an autosomal dominant disorder, resulting in low-density lipoprotein (LDL) receptor dysfunction. The prevalence of FH is estimated to be approximately, 1 in 200 and 1 in 170,000 among heterozygotes and homozygotes, respectively ( 1 ). Since FH patients develop severe coronary-artery disease (CAD) due to hypercholesterolemia in early adult life, lipid-lowering treatments must be started at childhood ( 2 ). Although pediatric FH is clinically diagnosed based on the serum LDL cholesterol (LDL-C) levels and a family history of hypercholesterolemia, genetic analysis is useful for a definitive diagnosis, as it can predict the risk stratification of CAD ( 3 , 4 ) and assist in early diagnosis and intervention, leading to improved prognosis. Here, we present a novel mutation in the LDLR gene, in a patient with heterozygous FH (HeFH). Patient Report The study subject was an 11-yr-old Japanese boy with Down’s syndrome. He was delivered at 36 wk and 4 d of gestation by cesarean section, due to a history of cesarean birth. His birth weight was 2,160 g (mean –2.1 standard deviation, SD, in Japan), and his body length was 41.0 cm (–3.8 SD). Down’s syndrome was diagnosed based on his facial appearance and genetic analysis. His old brother, mother, maternal uncles, maternal grandmother, maternal grandaunt, and maternal great-grandfather had been diagnosed with hypercholesterolemia. His mother was hypercholesterolemic (serum total cholesterol; TC level 308 mg/dL, LDL-C level 259 mg/dL) at the age of 48 yr. His maternal uncles and maternal grandmother were receiving HMG-CoA reductase inhibitors (statins) for their hypercholesterolemia, but they were hypercholesterolemic despite statin therapy. His older maternal uncle’s serum TC level was unknown, and LDL-C level was 136 mg/dL, at 55 yr of age. His younger maternal uncle’s serum TC level was 220 mg/dL, and LDL-C level was 116 mg/dL, at 52 yr of age. His maternal grandmother’s serum TC level 205 mg/dL, and LDL-C level was 112 mg/dL, at 80 yr of age. The serum lipid values of the other patients in the family were not available ( Fig. 1 Fig. 1. Pedigree of a Japanese family with familial hypercholesterolemia. Squares and circles indicate males and females, respectively. Black symbols represent individuals with the hypercholesterolemia phenotype and open symbols represent unaffected individuals. The filled symbols indicate patients who were genetically analyzed. The double fill symbols indicate hypercholesterolemia without genetic diagnosis. The proband and his mother are marked by arrows. Roman numerals to the left of the pedigree indicate the generation. The columns under each symbol indicate, from top to bottom, TC and LDL-C concentration (mg/dL). ). Further, he had no family history of CAD associated death. The patient was referred to our hospital at 7 yr of age due to hypercholesterolemia (serum total cholesterol; TC level 264 mg/dL, LDL-C level 200 mg/dL). His height was 120.4 cm (approximately 0 SD for the Down’s syndrome patients) and his weight was 21.4 kg (approximately –2.0 SD for the Down’s syndrome patients) or –6.6% of the Japanese standard weight for his height. He did not have xanthoma or Achilles tendon thickening. His serum concentration of thyroid hormones was normal. Based on these findings, we diagnosed him as FH. With the help of his mother, we carried out a lifestyle treatment, which included a proper lipid diet and exercise, for several months. However, his hypercholesterolemia did not improve. Statin therapy (Rosuvastatin Calcium ~(??) 2.5 mg daily) was started at 10 yr of age, which improved his hypercholesterolemia (serum TC level from 232 to 184 mg/dL, and LDL-C level from 168 to 132 mg/dL in one month). In Japan, only pitavastatin had been approved as a treatment for children with HeFH. However, he had asymptomatic cholelithiasis without biliary atresia. We started him on rosuvastatin instead of pitavastatin, because pitavastatin was contraindicated for biliary atresia. Mutational Analysis This study was approved by the Institutional Review Board of the Tokyo Metropolitan Children’s Medical Center (H28b-179), and an informed consent was obtained from the patient’s parents. Genomic DNA was extracted from the peripheral blood leukocytes of the patient and his mother. We performed targeted-exome sequencing of seven genes ( LDLR, APOB, PCSK9, LDLRAP1, APOE, ABCG5, ABCG8 ), known to cause hypercholesterolemia, using a next-generation sequencer ( 5 ). We used PCR-direct sequencing to make the final determination of the mutation. We identified a novel c.1067A&T (p.Asp356Val) missense mutation in the LDLR gene of the patient and his mother. This mutation was not detected in any of the 150 healthy controls and was absent in the databases, including dbSNP, the 1,000 Genomes Project, Exome Variant Server, NHLBI Exome Sequencing Project, and the Human Genetic Variation Database (HGVD