Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia

Iacocca, Michael A.; Wang, Jian; Dron, Jacqueline S.; Robinson, John F.; McIntyre, Adam D.; Cao, Henian; Hegele, Robert A.

doi:10.1194/jlr.d079301

Cited by 69 publications

(61 citation statements)

References 28 publications

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“…CNVs were identified using the VarSeq-CNV caller algorithm following the methods and parameters described in detail previously. 25 CNV analysis could not be performed on the 1KG data, as BAM files were not available.…”

Section: Identification Of Rare Copy-number Variantsmentioning

confidence: 99%

Severe hypertriglyceridemia is primarily polygenic

Dron

Wang

Cao

et al. 2019

Journal of Clinical Lipidology

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BACKGROUND: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.METHODS: We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants.RESULTS: As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P , .0001) more likely to carry one of these types of genetic susceptibility compared with controls.CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare

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Section: Identification Of Rare Copy-number Variantsmentioning

confidence: 99%

Severe hypertriglyceridemia is primarily polygenic

Dron

Wang

Cao

et al. 2019

Journal of Clinical Lipidology

Self Cite

156

132

View full text Add to dashboard Cite

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“…Large CNVs were excluded by SNP‐array analysis with the CytoSNP‐850 K BeadChip human CytoSNP microarray (Illumina, CA). Genic and intragenic Copy Number Variants (CNVs) were excluded with the bioinformatics tool VarSeq CNV Caller (VarSeq V2.1.0; Golden Helix, MT) (Iacocca et al, ). The presence of deep intronic, noncoding variants in known CPHD genes has not been excluded.…”

Section: Case Reportmentioning

confidence: 99%

Loss of function BMP4 mutation supports the implication of the BMP/TGF‐β pathway in the etiology of combined pituitary hormone deficiency

Rodríguez-Contreras

Marbán-Calzón²,

Vallespín

et al. 2019

American J of Med Genetics Pt A

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Despite BMP4 signaling being critical to Rathke's pouch induction and maintenance during early stages of pituitary development, its implication in the etiology of combined pituitary hormone deficiency (CPHD) and other clinical presentations of congenital hypopituitarism has not yet been definitely demonstrated. We report here the first CPHD patient with a de novo pathogenic loss-of-function variant in BMP4. A 6-year-old boy, with macrocephaly, myopia/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism, was referred for genetic analysis of CPHD. Targeted NGS analysis with a custom panel (n = 310 genes) identified a novel heterozygous de novo nonsense variant, NM_001202.5: c.794G > A, p.(Trp265*) in BMP4, which introduces a premature stop codon in the BMP4 pro-domain, impairing the transcription of the TGF-β mature peptide domain. Additional relevant variants in other genes implicated in pituitary development signaling pathways such as SMAD4 and E2F4 (BMP/TGF-pathway), ALMS1 (NOTCH-pathway), and TSHZ1 (Prokineticin-pathway), were also identified. Our results support the implication of the BMP/TGF-β signaling pathway in the etiology of CPHD and suggest that oligogenic contribution of additional inherited variants may modify the phenotypic expressivity of BMP4 pathogenic variants. K E Y W O R D S BMP/TGF-β pathway, BMP4, combined pituitary hormone deficiency, hypopituitarism, NGS

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“…This strengthens the value of the concomitant detection of CNV by this new strategy, as has been recently described. 27 It is of note that with the previous strategy, MLPA was only performed in negative patients with DLCNC score above 5 for economic reasons; thus CNV would not have been identified in 2 patients. Moreover, for molecular diagnosis of HTG, the approach used herein identified a CNV in LPL gene, which would not had been detected either with our previous strategy and yet to be reported using other NGS strategies published in the field.…”

Section: Discussionmentioning

confidence: 99%

Single, short in‐del, and copy number variations detection in monogenic dyslipidemia using a next‐generation sequencing strategy

et al. 2018

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Optimal molecular diagnosis of primary dyslipidemia is challenging to confirm the diagnosis, test and identify at risk relatives. The aim of this study was to test the application of a single targeted next-generation sequencing (NGS) panel for hypercholesterolemia, hypocholesterolemia, and hypertriglyceridemia molecular diagnosis. NGS workflow based on a custom AmpliSeq panel was designed for sequencing the most prevalent dyslipidemia-causing genes (ANGPTL3, APOA5, APOC2, APOB, GPIHBP1, LDLR, LMF1, LPL, PCSK9) on the Ion PGM Sequencer. One hundred and forty patients without molecular diagnosis were studied. In silico analyses were performed using the NextGENe software and homemade tools for detection of copy number variations (CNV). All mutations were confirmed using appropriate tools. Eighty seven variations and 4 CNV were identified, allowing a molecular diagnosis for 40/116 hypercholesterolemic patients, 5/13 hypocholesterolemic patients, and 2/11, hypertriglyceridemic patients respectively. This workflow allowed the detection of CNV contrary to our previous strategy. Some variations were found in previously unexplored regions providing an added value for genotype-phenotype correlation and familial screening. In conclusion, this new NGS process is an effective mutation detection method and allows better understanding of phenotype. Consequently this assay meets the medical need for individualized diagnosis of dyslipidemia.

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Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia

Cited by 69 publications

References 28 publications

Severe hypertriglyceridemia is primarily polygenic

Severe hypertriglyceridemia is primarily polygenic

Loss of function BMP4 mutation supports the implication of the BMP/TGF‐β pathway in the etiology of combined pituitary hormone deficiency

Single, short in‐del, and copy number variations detection in monogenic dyslipidemia using a next‐generation sequencing strategy

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