title: Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing.
abstract: Familial hypercholesterolaemia (FH) is a serious genetic metabolic disease. We identified a specific family in which the proband had typical homozygous phenotype of FH, but couldn't detect any mutations in usual pathogenic genes using traditional sequencing. This study is the first attempt to use whole exome sequencing (WES) to identify the pathogenic genes in Chinese FH. The routine examinations were performed on all parentage members, and WES on 5 members. We used bioinformatics methods to splice and filter out the pathogenic gene. Finally, Sanger sequencing and cDNA sequencing were used to verify the candidate genes. Half of parentage members had got hypercholesterolaemia. WES identified LDLR IVS8[-10] as a candidate mutation from 222,267 variations. The Sanger sequencing showed proband had a homozygous mutation inherited from his parents, and this loci were cosegregated with FH phenotype. The cDNA sequencing revealed that this mutations caused abnormal shearing. This mutation was first identified in Chinese patients, and this homozygous mutation is a new genetic type of FH. This is the first time that WES was used in Chinese FH patients. We detected a novel genetic type of LDLR homozygous mutation. WES is powerful tools to identify specific FH families with potentially pathogenic gene mutations.
authors.affiliation: 1] Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases. The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Department of Atherosclerosis, Beijing 100029, China [2] Beijing AnZhen Hospital, Affiliated to Capital Medical University, Department of Dermatology, Beijing 100029, China.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Sun
authors.affiliation: Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yong-Biao
authors.initials: YB
authors.lastname: Zhang
authors.affiliation: Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases. The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Department of Atherosclerosis, Beijing 100029, China.
authors.forename: Long
authors.initials: L
authors.lastname: Jiang
authors.affiliation: 1] Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wan
authors.affiliation: Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases. The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Department of Atherosclerosis, Beijing 100029, China.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Wu
authors.affiliation: Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases. The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Department of Atherosclerosis, Beijing 100029, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
authors.affiliation: Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: 1] Institute of Genomics, Chinese Academy of Sciences and Key Laboratory of Genome Science and Information, Chinese Academy of Sciences, Beijing 100101, China [2] National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, Jilin, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Beijing AnZhen Hospital, Affiliated to Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases. The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Department of Atherosclerosis, Beijing 100029, China.
authors.forename: Lu-Ya
authors.initials: LY
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002675:Child, Preschool; D002681:China; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D007438:Introns; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: C573412:LDLR protein, human; D011973:Receptors, LDL