A case of familial hypercholesterolemia caused by homozygous deletion in the <i>LDLR</i> gene diagnosed by targeted next-generation sequencing

Melinkeri, Rashida Patanwala; Agarwal, Meenal; Anand, Siddharth; Sawant, Vishal; Singla, Ritu

doi:10.1080/26415321.2019.1670555

Cited by 1 publication

(3 citation statements)

References 28 publications

(33 reference statements)

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“…The entire study group was characterized by very high levels of TC and LDL-c with mean concentrations of 388 mg/dL (10.03 mmol/L) and 318 mg/dL (8.22 mmol/L), respectively. These findings correlate with previous reports that heterozygous LDLR CNVs are associated with a more severe biochemical phenotype than other types of alteration [ 21 ].…”

Section: Discussionsupporting

confidence: 92%

“…Various single or multi-exon deletions in the LDLR gene have been reported so far (exons 2–3, exon 5, exon 7, exon 9–14) [ 21 ]; however, this is the first report of a heterozygous deletion of exons 9 and 10 co-occurring with SNV. Exons 7–14 of the LDLR gene encode the EGF-precursor homology domain, that plays a pivotal role in lipoprotein release during receptor recycling.…”

Section: Discussionmentioning

confidence: 99%

“…Exons 7–14 of the LDLR gene encode the EGF-precursor homology domain, that plays a pivotal role in lipoprotein release during receptor recycling. The amino acid sequence in this domain is highly conserved, with 70–85% sequence homology shared across different species: human, cow, rabbit, hamster, rat, and the toad Xenopus laevis [ 21 ]. Any change within the domain may result in impaired release of LDL from the LDLR and potentially prevent the return of the receptor to the hepatocyte surface.…”

Section: Discussionmentioning

confidence: 99%

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Identification of New Copy Number Variation and the Evaluation of a CNV Detection Tool for NGS Panel Data in Polish Familial Hypercholesterolemia Patients

Rutkowska

Pinkier

Sałacińska

et al. 2022

Genes

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Familial hypercholesterolemia (FH) is an inherited, autosomal dominant metabolic disorder mostly associated with disease-causing variant in LDLR, APOB or PCSK9. Although the dominant changes are small-scale missense, frameshift and splicing variants, approximately 10% of molecularly defined FH cases are due to copy number variations (CNVs). The first-line strategy is to identify possible pathogenic SNVs (single nucleotide variants) using multiple PCR, Sanger sequencing, or with more comprehensive approaches, such as NGS (next-generation sequencing), WES (whole-exome sequencing) or WGS (whole-genome sequencing). The gold standard for CNV detection in genetic diagnostics are MLPA (multiplex ligation-dependent amplification) or aCGH (array-based comparative genome hybridization). However, faster and simpler analyses are needed. Therefore, it has been proposed that NGS data can be searched to analyze CNV variants. The aim of the study was to identify novel CNV changes in FH patients without detected pathogenic SNVs using targeted sequencing and evaluation of CNV calling tool (DECoN) working on gene panel NGS data; the study also assesses its suitability as a screening step in genetic diagnostics. A group of 136 adult and child patients were recruited for the present study. The inclusion criteria comprised at least “possible FH” according to the Simon Broome diagnostic criteria in children and the DLCN (Dutch Lipid Clinical Network) criteria in adults. NGS analysis revealed potentially pathogenic SNVs in 57 patients. Thirty selected patients without a positive finding from NGS were subjected to MLPA analysis; ten of these revealed possibly pathogenic CNVs. Nine patients were found to harbor exons 4–8 duplication, two harbored exons 6–8 deletion and one demonstrated exon 9–10 deletion in LDLR. To test the DECoN program, the whole study group was referred for bioinformatic analysis. The DECoN program detected duplication of exons 4–8 in the LDLR gene in two patients, whose genetic analysis was stopped after the NGS step. The integration of the two methods proved to be particularly valuable in a five-year-old girl presenting with extreme hypercholesterolemia, with both a pathogenic missense variant (c.1747C>T) and exons 9–10 deletion in LDLR. This is the first report of a heterozygous deletion of exons 9 and 10 co-occurring with SNV. Our results suggest that the NGS-based approach has the potential to identify large-scale variation in the LDLR gene and could be further applied to extend CNV screening in other FH-related genes. Nevertheless, the outcomes from the bioinformatic approach still need to be confirmed by MLPA; hence, the latter remains the reference method for assessing CNV in FH patients.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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