A novel mutation of the LDL receptor gene leading to familial hypercholesterolemia

Su, Pengyu; Wang, Luya; Lin, Jie; Liu, Shu; Xia, Jian‐Bai; Xu, Yingjie; Qiang, Yong; Yang, Yanling; Pan, Xiaodong; Li, Du; Qin, Yanwen; Wu, Zhiyi

doi:10.1002/ejlt.200800196

Cited by 3 publications

(3 citation statements)

References 26 publications

(25 reference statements)

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“…Abbreviations: APOB, apolipoprotein B; FH, familial hypercholesterolemia; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9 one mutation in the APOB gene and one mutation in the PCSK9 gene were also detected. All mutations were assessed as pathogenic by previous functional studies[17][18][19] and by reference to online databases (MutationTaster,20 ClinVar 21 ). At diagnosis, the mean age of the index children was 9.1 AE 4.8 years, and the mean untreated LDL-C level was 15.1 AE 3.8 mmol/L; 54% had CAD, 95% had carotid atherosclerosis and peripheral vascular disease, 23% had hypertension, and none had diabetes mellitus.…”

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confidence: 99%

Reverse cascade screening for familial hypercholesterolemia in high‐risk Chinese families

Pang

Wang

et al. 2017

Clinical Cardiology

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Background Reverse cascade screening is not commonly employed to detect new cases of familial hypercholesterolemia (FH). We aimed to assess the outcome of this screening strategy in families in which the probands were children with severe FH. Hypothesis Reverse cascade screening is an effective method to detect new patients with FH. Methods Reverse cascade screening was undertaken starting from 47 index children with severe hypercholesterolemia; 39 were homozygous/compound heterozygous FH and 8 were heterozygous FH. Available parents, siblings, and second‐degree relatives were contacted and screened. Results From the 39 cases of homozygous/compound heterozygous FH, 80 first‐degree family members were available for screening; 70 were parents and 10 were siblings. All first‐degree relatives screened were genetically diagnosed with FH. None of the parents had been treated with statins at the time of diagnosis, and 10 (12.7%) had premature coronary artery disease. Additionally, 46 second‐degree relatives were screened, of which 41 (89%) were diagnosed with FH. From the 8 heterozygous FH children, 17 first‐ and second‐degree relatives were screened and 12 new cases of FH were also diagnosed. Hence, the overall diagnostic yield of screening was 2.8 new cases of FH per index case. Conclusions Reverse cascade screening is a highly effective method for diagnosing new cases of FH in parents, siblings, and second‐degree relatives of index children with severe FH.

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confidence: 99%

Reverse cascade screening for familial hypercholesterolemia in high‐risk Chinese families

Pang

Wang

et al. 2017

Clinical Cardiology

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“…Many mutations were also identified in pathogenic genes, such as apolipoprotein B ( apoB ) and proprotein convertase subtilisin/kexin type 9 gene ( PCSK9 ), of ADH 10 . We also identified several potential relevant pathogenic mutations in LDLR , apoB and PCSK9 for FH 11 12 13 14 15 16 . These data may reveal the genetic mechanisms underlying FH and increase the knowledge of FH in the Han Chinese population.…”

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Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing

Sun

Zhang

Jiang

et al. 2015

Sci Rep

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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.

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“…DNA samples from 12 patients were processed using DNA resequencing array7, samples from 14 patients were processed by targeted exome sequencing10, and samples from 6 patients were processed by both methods. Some probands were reported in previous studies11132526. This study was approved by the Research Ethics Committee of Beijing Anzhen Hospital in China.…”

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confidence: 99%

The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia

Jiang

Sun

et al. 2016

Sci Rep

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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.

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A novel mutation of the LDL receptor gene leading to familial hypercholesterolemia

Cited by 3 publications

References 26 publications

Reverse cascade screening for familial hypercholesterolemia in high‐risk Chinese families

Reverse cascade screening for familial hypercholesterolemia in high‐risk Chinese families

Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing

The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia

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