The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder. Although genetic testing is an important tool for detecting FH-causing mutations in patients, diagnostic methods for young patients with severe hypercholesterolemia are understudied. This study compares the target exome sequencing (TES) technique with the DNA resequencing array technique on young patients with severe hypercholesterolemia. A total of 20 unrelated patients (mean age 14.8 years) with total cholesterol > 10 mmol/L were included. 12 patient samples were processed by DNA resequencing array, 14 patient samples were processed by TES, and 6 patient samples were processed by both methods. Functional characterization of novel mutations was performed by flow cytometry. The mutation detection rate (MDR) of DNA resequencing array was 75%, while the MDR of TES was 100%. A total of 27 different mutations in the LDLR were identified, including 3 novel mutations and 8 mutations with previously unknown pathogenicity. Functional characterization of c.673delA, c.1363delC, p.Leu575Phe and p.Leu582Phe variants found that all of them are pathogenic. Additionally, 7 patients were diagnosed with Heterozygous FH (HeFH) in which lipid levels were significantly higher than common HeFH patients. This data indicates that TES is a very efficient tool for genetic diagnosis in young patients with severe hypercholesterolemia.
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.|Department of Cardiovascular, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.
Long
L
Jiang
Department of Emergency Intensive Care Unit, Beijing AnZhen Hospital, Capital Medical University, Beijing, 100029, China.
Wen-Feng
WF
Wu
Department of Dermatology, Beijing AnZhen Hospital, Capital Medical University, Beijing, 100029, China.
Li-Yuan
LY
Sun
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.|University of South China, Hengyang, 421001, China.
Pan-Pan
PP
Chen
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.|The Affiliated Hospital of North China University of Science and Technology, North China University of Science and Technology, Tangshan, 063000, Hebei Province, China.
Wei
W
Wang
Biofisika Institute (UPV/EHU, CSIC) and Dpt. Biochemistry and Molecular Biology, University of the Basque Country, UPV/EHU, Spain.
Asier
A
Benito-Vicente
School of Computer Engineering, Nanyang Technological University, 639798, Singapore.
Fan
F
Zhang
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
Xiao-Dong
XD
Pan
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
Wei
W
Cui
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
Shi-Wei
SW
Yang
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
Yu-Jie
YJ
Zhou
Biofisika Institute (UPV/EHU, CSIC) and Dpt. Biochemistry and Molecular Biology, University of the Basque Country, UPV/EHU, Spain.
Cesar
C
Martin
Department of Atherosclerosis, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
Lu-Ya
LY
Wang
D000293:Adolescent; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006937:Hypercholesterolemia / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D008297:Male; D025202:Molecular Diagnostic Techniques; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
D011973:Receptors, LDL