Evidence map›Paper›PMID 31617323›Full record

ArticleMolecular genetics & genomic medicine2019

Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.

Karen H Y Wong, Michal Levy-Sakin, Walfred Ma, Nina Gonzaludo, Angel C Y Mak, Dedeepya Vaka, Annie Poon, Catherine Chu, Richard Lao, Melek Balamir and 6 more

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular genetics & genomic medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Article
  2. Journal of the American Heart Association · 2023
    Article
  3. Article
  4. Article
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Karen H Y WongCardiovascular Research Institute, University of California, San Francisco, CA, USA.ORCID 0000-0002-1648-1414
Michal Levy-SakinCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Walfred MaCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Nina GonzaludoCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Angel C Y MakCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Dedeepya VakaInstitute for Human Genetics, University of California, San Francisco, CA, USA.
Annie PoonInstitute for Human Genetics, University of California, San Francisco, CA, USA.
Catherine ChuInstitute for Human Genetics, University of California, San Francisco, CA, USA.
Richard LaoInstitute for Human Genetics, University of California, San Francisco, CA, USA.
Melek BalamirDepartment of Internal Medicine, Istanbul University, Istanbul, Turkey.
Zoe GrenvilleCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Nicolas WongCardiovascular Research Institute, University of California, San Francisco, CA, USA.
John P KaneCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Pui-Yan KwokCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Mary J MalloyCardiovascular Research Institute, University of California, San Francisco, CA, USA.
Clive R PullingerCardiovascular Research Institute, University of California, San Francisco, CA, USA.

Funding

Single molecule DNA mapping for genome and CNV analysisR01HG005946 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KWOK, PUI-YAN, XIAO, MING · 2010 to 2021
$6.5M
NHGRI NIH HHS R01 HG005946
6 · The paper itself

Abstract

backgroundHomozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis.

objectiveWe aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds.

methodsWe applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked-Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR-based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL.

resultsIn the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs.

conclusionsWhile the application of WES can provide a cost-effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked-Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.

Indexed as

Base SequenceChild, PreschoolCholesterol, LDLChromosome MappingCohort StudiesExome SequencingFrameshift MutationGenetic VariationGenome, HumanHeterozygoteHomozygoteHumansHyperlipoproteinemia Type IIInfantLipoproteins, LDLPedigreeCholesterol, LDLLDLR protein, humanLipoproteins, LDLReceptors, LDL10xG linked-reads whole genome sequencingdyslipidemiaLDLwhole exome sequencing

Identifiers

PMID31617323
PMCPMC6900368

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.