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Cited by 133Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation

Open access
Marduel, Marie, Ouguerram, Khadija, Serre, Valérie, Bonnefont-Rousselot, Dominique, Marques-Pinheiro, Alice, Erik Berge, Knut, Devillers, Martine, Luc, Gérald +14 more·2013·Human Mutation
DOI 10.1002/humu.22215PMC PMC3638718
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Abstract

Apolipoprotein (apo) E mutants are associated with type III hyperlipoproteinemia characterized by high cholesterol and triglycerides levels. Autosomal dominant hypercholesterolemia (ADH), due to the mutations in the LDLR, APOB, or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to the high levels of low-density lipoproteins (LDLs). We now report an exceptionally large family including 14 members with ADH. Through genome-wide mapping, analysis of regional/functional candidate genes, and whole exome sequencing, we identified a mutation in the APOE gene, c.500_502delTCC/p.Leu167del, previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p.Leu167del in ADH, with (1) a predicted destabilization of an alpha-helix in the binding domain, (2) a decreased apo E level in LDLs, and (3) a decreased catabolism of LDLs. Our results show that mutations in the APOE gene can be associated with bona fide ADH.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper reports an exceptionally large French family with autosomal dominant hypercholesterolemia (ADH) in which linkage mapping and exome sequencing identified the APOE p.Leu167del mutation as the likely cause. The authors conclude that APOE mutations can be associated with bona fide ADH and that APOE screening is warranted alongside LDLR, APOB, and PCSK9 in ADH molecular diagnosis.

Key findings

  • In the HC126 family, genome-wide linkage gave a maximum LOD score of 2.55 (θ=0) at rs718087 on chromosome 19; multipoint analysis at 19q13.31–13.32 gave a maximum LOD score of 3.15 between rs1988065 and rs3513657 (19:43,374,601–45,439,163).
  • The APOE c.500_502delTCC (p.Leu167del) mutation was identified and was not detected in over 220 controls. Additional APOE variants p.Arg269Gly and p.Arg235Trp were found in non-LDLR/APOB/PCSK9 probands and were absent in over 500 French controls.
  • Two p.Leu167del carriers had total apo E levels of 4.09 mg/dL and 4.03 mg/dL, both within the normal range (2.30–6.30 mg/dL); apo E distribution showed a higher proportion in HDL (77% vs 63–69%) and a lower proportion in LDL (12% vs 18–25%).
  • In one carrier after a 2-month washout, lipid values were triglycerides 3.7, total cholesterol 10.5, LDL-cholesterol 8.1, and HDL-cholesterol 0.7 mmol/L; LDL kinetics resembled those of familial hypercholesterolemia patients, with an increased LDL pool due to increased LDL production and decreased LDL catabolism. No splenomegaly or thrombocytopenia was present in the 12 APOE p.Leu167del carriers of HC126 nor in the proband of HC512.

Methods

  • ADH families were recruited by the French National Research Network on Hypercholesterolemia; the HC126 family was initiated through proband II-2 and expanded to 27 individuals over 3 generations, exploring 23 meioses. Inclusion criteria included total and LDL-cholesterol above the 95th percentile, triglycerides below 1.5 mmol/L, and personal and/or documented familial xanthomas and/or early coronary artery disease.
  • The study combined genome-wide linkage mapping (with 100,000 simulations; av.ELOD 2.1, max.ELOD 4.8), regional microsatellite/multipoint analysis, candidate gene sequencing, and whole exome sequencing in three affected members (III-2, III-7, III-8).
  • APOE p.Leu167del was screened by direct fluorescent PCR in controls, and the APOE gene was sequenced in 153 non-LDLR/APOB/PCSK9 probands (55 French ADH and 98 Norwegian hyperlipidemics). The authors also performed homology modeling, measured apo E levels and lipoprotein distribution, and conducted in vivo apo B-100 kinetic studies in one patient after washout.

Limitations

  • Stated: the apo E distribution data need confirmation because they are based on only two patients, including one under lipid-lowering therapy; the kinetic data need confirmation because they are based on only one patient.
  • Stated: a LDL receptor-binding defect could not be directly excluded, and a prior in vitro competitive binding test with apo E from a heterozygous p.Leu167del carrier showed no significant binding defect, so the effect of the deleted mutant alone could not be observed.
  • Evident: the small number of mutation carriers limits biochemical and kinetic conclusions; the family also includes possible phenocopies (I-3 and II-14) and an unclassified patient (II-5), suggesting another lipid abnormality in the family remains unidentified.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/humu.22215

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 27 cited sources checked · 1 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    Among 9 non-LDLR/-APOB/-PCSK9/-HCHOLA4 families identified, one was large enough to enable genome wide mapping of a new ADH gene.

    “Among 9 non-LDLR/-APOB/-PCSK9/-HCHOLA4 families we have identified, one was large enough to enable genome wide mapping of a new ADH gene (Marques-Pinheiro A et al. 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Marques-Pinheiro A et al. 2010 source

      The Abstract and Linkage analysis section distinguish the large family used to map HCHOLA4 from the nine families that excluded linkage to that locus. The paper therefore does not place the genome-mapped family among those nine; it says the opposite. Our copy provides no page numbers for these passages. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    At least 19% of ADH families have disease not associated with a mutation within LDLR, APOB or PCSK9.

    “at least 19% of ADH families in which the disease is not associated with a mutation within one of these three genes (Marduel M et al. 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Marduel M et al. 2010 source

      The Results and Discussion report that no mutation in LDLR, APOB or PCSK9 was identified in 258 of 1,358 French ADH probands (19.0%). This supports the percentage for that cohort, but the claim extends it to ADH families generally and treats an unidentified mutation as evidence that no mutation in those genes is associated with their disease. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Findingown data

    Regional haplotype construction identified a common region for affected members from D19S417 to D19S908.

    “Regional haplotype construction allowed the identification of a common region for affected members from D19S417 to D19S908 (Figure 1A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Phenotypically unclassified patient II-5 did not carry the familial-disease haplotype.

    “Phenotypically unclassified patient II-5 did not carry the familial-disease haplotype”
    Quote in the paperSubstantial claim
  • Findingown data

    Through genome wide mapping, analysis of regional/functional candidate genes and whole exome sequencing, the authors identified a mutation in the APOE gene, p.Leu167del.

    “Through genome wide mapping, analysis of regional/functional candidate genes and whole exome sequencing, we identified a mutation in the APOE gene, p.Leu167del”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 24
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    New ADH loci were recently mapped at 16q22.1 (HCHOLA4) and 8q24.22.

    “new ADH loci were recently mapped at 16q22.1, HCHOLA4 (Marques-Pinheiro A et al. 2010), and 8q24.22 (Cenarro A et al. 2011).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Marques-Pinheiro A et al. 2010 source
    • cites Cenarro A et al. 2011 source

  • May combine two claims.

    Findingcitation

    VLDL and IDL kinetic parameters in HC126-II-3 were in accordance with the high triglyceride level only observed for this measurement, showing similarities with type III hyperlipoproteinemia (E2E2 genotype) such as dramatically increased VLDL and IDL pool due to a decreased conversion rate.

    “VLDL and IDL kinetic parameters were in accordance with the high triglyceride level only observed for this measurement, and never before in this patient, showing similarities with a type III hyperlipoproteinemia (E2E2 genotype) such as the dramatically increased VLDL and IDL pool due to a decreased conversion rate (Ooi EM et al. 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ooi EM et al. 2010 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Leu167 of apoE is not a conserved amino acid, but is the fourth residue in a 6 amino acid motif of which positions 1, 2, 3 and 6 are very well conserved from Xenopus tropicalis to Homo sapiens.

    “Leu167 of apoE is not a conserved amino acid, but is the fourth residue in a 6 amino acid motif of which positions 1, 2, 3 and 6 are very well conserved from Xenopus tropicalis to Homo sapiens (Supp. Figure S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No splenomegaly or thrombocytopenia were present in the 12 APOE p.Leu167del carriers of the HC126 family nor in the proband of HC512, indicating that these subjects did not present the sea-blue histiocytosis disease.

    “No splenomegaly or thrombocytopenia were present in the 12 APOE p.Leu167del carriers of the HC126 family nor in the proband of HC512 indicating that these subjects did not present the sea-blue histiocytosis disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The APOE p.Leu167del was not detected in over 220 controls, indicating that this apo E variation is not a frequent polymorphism.

    “The APOE p.Leu167del was not detected in over 220 controls, in agreement with Faivre et al. who had investigated 50 French controls, and indicating that this apo E variation is not a frequent polymorphism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Faivre L et al. 2005 source

  • May combine two claims.

    Findingcitation

    The CCDC123 p.Arg146Gln and RHPN2 p.Gln384Arg variants are frequent genomic variants, excluding them as possible disease-causing mutations.

    “The two first variants were shown to be frequent genomic variants (//snp.gs.washington.edu/EVS/, //www.1000genomes.org), excluding them from being a possible disease-causing mutation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The HC126 family was recruited through proband II-2 and expanded to 27 individuals over 3 generations, exploring 23 meioses.

    “The recruitment of the HC126 family was initiated through the female proband II-2, and expanded to 27 individuals over 3 generations, thus exploring 23 meioses (Figure 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The increased VLDL and IDL pool for the HC126 patient was also due to an increased production rate, not observed for E2E2 patients, but already reported for patients carrying a PCSK9 gene mutation.

    “Interestingly, the increased VLDL and IDL pool for the HC126 patient was also due to an increased production rate, that was not observed for E2E2 patients, but already reported for patients carrying a PCSK9 gene mutation (Ouguerram K et al. 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ouguerram K et al. 2003 source

  • May combine two claims.

    Findingown data

    Apo E distribution in lipoprotein fractions showed a higher proportion in HDL (77% vs 63-69%) and a lower proportion in LDL (12% vs 18-25%) in p.Leu167del carriers.

    “Apo E distribution in each lipoprotein fraction showed a higher proportion in HDL (77% vs 63–69%), and a lower proportion in LDL (12% vs 18–25%) (Supp. Table S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LDL kinetic parameters in HC126-II-3 were similar to those from FH patients (LDLR mutation) with an increased LDL pool, due to both an increase in LDL production rate and a decrease in LDL catabolism.

    “LDL kinetic parameters were similar to those from FH patients (mutation in the LDLR gene) with an increased LDL pool, which was the consequence of both an increase in LDL production rate and a decrease in LDL catabolism (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The CEACAM8 p.Asn219Lys variant is rare (3/10755 in Exome Variant Server) and not reported by the 1000 genome project.

    “The CEACAM8 variant is rare, 3/10755 in the Exome Variant Server and not reported by the “1000 genome” project.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Rare apo E mutants have been described associated with type III hyperlipoproteinemia or lipoprotein glomerulopathy.

    “rare apo E mutants have been described associated with type III hyperlipoproteinemia or lipoprotein glomerulopathy (OMIM +611771).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites OMIM +611771

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The APOE p.Leu167del mutation was previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia.

    “previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Nguyen TT et al. 2000 source
    • cites Faivre L et al. 2005 source
    • cites Solanas-Barca M et al. 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Apo E2 isoform is associated with lower LDL cholesterol, except for 5% of E2/E2 carriers who develop type III hyperlipoproteinemia.

    “Apo E2 isoform is associated with lower LDL cholesterol, except for 5% of E2/E2 carriers who develop type III hyperlipoproteinemia (OMIM +107741)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites OMIM +107741

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ADH is genetically heterogeneous and associated with mutations in LDLR, APOB and PCSK9.

    “ADH is genetically heterogeneous and associated with mutations in the well-known LDLR (low density lipoprotein receptor) (FH, OMIM #606945), APOB (apolipoprotein B-100) (FDB, OMIM # 144010) and PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9, Abifadel M et al. 2003) genes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abifadel M et al. 2003 source

  • May combine two claims.

    Interpretationreasoning

    IDL production is increased and, combined with low IDL catabolism, leads to increased LDL production.

    “Accordingly, IDL production is increased and, combined to the low IDL catabolism, leads to an increased LDL production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The APOE p.Leu167del mutation was reported in subjects with FCHL and in the HC126 family reported here with a bona fide ADH.

    “The APOE p.Leu167del mutation was reported in subjects with familial combined hyperlipidemia (FCHL, type III dyslipoproteinemia) (Solanas-Barca M et al. 2012) and in the HC126 family reported here with a bona fide ADH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Solanas-Barca M et al. 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Apo E4 isoform is associated with elevated total and LDL-cholesterol levels, due to the higher affinity of apo E4 for VLDL and LDL.

    “Apo E4 isoform is associated with elevated total and LDL-cholesterol levels, due to the higher affinity of apo E4 for VLDL and LDL”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hatters DM et al. 2006 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A few rare apo E variants (p.Glu21Lys, p.Pro102Arg, p.Leu270Glu) have been observed in probands with hyperLDLemia, but none co-segregated with hyperLDLemia in the families.

    “a few rare apo E variants (p.Glu21Lys, p.Pro102Arg and, p.Leu270Glu) have been observed in probands with hyperLDLemia (type IIa hyperlipoproteinemia), but none co-segregated with hyperLDLemia in the families (Wardell MR et al. 1991, van den Maagdenberg AM et al. 1993).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wardell MR et al. 1991 source
    • cites van den Maagdenberg AM et al. 1993

  • Classified as probably not a substantial claim.

    Study design and conductown data

    These apo E distribution data need to be confirmed because they are based on only two patients, including one under lipid lowering therapy.

    “However, these data need to be confirmed because they are based on the study of only two patients, including one under a lipid lowering therapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The other mutations, p.Arg235Trp and p.Arg269Gly, are at the origin of a loss of charge in the first and second α helices of the C-terminal domain that very probably change each helix's properties, interaction with lipoproteins, and receptor binding.

    “The other mutations, p.Arg235Trp and p.Arg269Gly, are at the origin of a loss of charge in the first and second α helices of the C-terminal domain that very probably change each helix’s properties, interaction with lipoproteins, and receptor binding.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    These kinetic data need to be confirmed because they are based on the study of only one patient.

    “However, these data need to be confirmed because they are based on the study of only one patient.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The p.Arg269Gly apo E mutant has been previously reported in a proband with type IIb hyperlipoproteinemia, differing from ADH by elevated plasma triglyceride levels.

    “The p.Arg269Gly apo E mutant has been previously reported in a proband with type IIb hyperlipoproteinemia, differing from ADH by elevated plasma triglyceride levels (Wardell MR et al. 1991).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wardell MR et al. 1991 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Apo E3 and apo E4 bind with similarly high affinity to the LDL receptor, whereas apo E2 binding is 50- to 100-times weaker.

    “Whereas apo E3 and apo E4 bind with similarly high affinity to the LDL receptor, the binding of apo E2 is 50- to 100- times weaker (Weisgraber KH et al. 1982).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Weisgraber KH et al. 1982 source

  • May combine two claims. The quote only partly states this claim.

    Interpretationown data

    Two affected members I-3 and II-14 did not carry the familial-disease haplotype and highly probably display a phenocopy form of ADH.

    “as well as the two affected members I-3 and II-14 who highly probably display a phenocopy form of ADH”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The APOE gene accounts for a significant fraction of the variation in plasma cholesterol levels.

    “The APOE gene accounts for a significant fraction of the variation in plasma cholesterol levels (Eichner JE et al. 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Eichner JE et al. 2002 source

  • May combine two claims.

    Interpretationreasoning

    Both hypotheses (decreased affinity of apo E mutant to LDL receptor; increased LDL production related to increased apo B-100 flux from VLDL) are in agreement with a decreased catabolism of LDL bearing apo E p.Leu167del and thus explaining the hyperLDLemia observed in the family.

    “Altogether, both hypotheses are in agreement with a decreased catabolism of LDL bearing apo E p.Leu167del and thus explaining the hyperLDLemia observed in the family.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Mutations in LDLR or APOE gene may amplify the effect of these factors, and thus, according to the number or nature of these factors, could be associated with an overlapping phenotype between FCHL and ADH.

    “Mutations in the LDLR or APOE gene may amplify the effect of these factors, and thus, according to the number or the nature of these factors, could be associated with an overlapping phenotype between FCHL and ADH.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    LDL kinetic parameters of the apo E mutant carrier were similar to those from FH patients, strengthening the very probable effect of LDL bearing an apo E mutant on their catabolism.

    “LDL kinetic parameters of apo E mutant carrier were similar to those from FH patients strengthening the very probable effect of LDL bearing an apo E mutant on their catabolism.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    ADH due to mutations in LDLR, APOB or PCSK9 is characterized by an isolated elevation of cholesterol due to high levels of low-density lipoproteins (LDL).

    “Autosomal Dominant Hypercholesterolemia (ADH), due to mutations in the LDLR, APOB or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to high levels of low-density lipoproteins (LDL).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Abifadel M et al. 2003 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The APOE p.Leu167del mutation was reported to be associated with sea-blue histiocytosis.

    “The APOE p.Leu167del mutation was reported to be associated with sea-blue histiocytosis (OMIM #26960)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites OMIM #26960

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The electrostatic surface charges are altered in apo E p.Leu167del, likely influencing interaction with lipids and affinity of apo E to its receptors.

    “The electrostatic surface charges are altered in apo E p.Leu167del, that also likely influences interaction with lipids and affinity of apo E to its receptors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The APOE p.Leu167del mutation was reported in subjects with familial combined hyperlipidemia (FCHL).

    “The APOE p.Leu167del mutation was also reported in subjects with familial combined hyperlipidemia (FCHL, type III dyslipoproteinemia) (Solanas-Barca M et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Solanas-Barca M et al. 2012 source
33 of 33

  • The authors state this as an assumption.

    A compensatory increased activity of the normal apoE in the presence of the deleted mutant could mask a LDL receptor-binding defect.

    “under the hypothesis of a compensatory increased activity of the normal apoE in the presence of the deleted mutant”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • FH due to APOE deficiency is recessively inherited, as in APOE-deficient homozygotes, but APOE variants diagnosed as ADH have also been reported.

    “FH due to APOE deficiency is recessively inherited, as in APOE-deficient homozygotes, but APOE variants diagnosed as ADH have also been reported29).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]

    The Abstract reports an APOE p.Leu167del mutation in a family with autosomal dominant hypercholesterolemia, supporting the second part of the sentence. The passages found do not establish that FH due to APOE deficiency is recessively inherited or describe APOE-deficient homozygotes. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Whole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH.

    “Subsequently, whole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH29, 57, 118).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]

    The Abstract reports whole-exome sequencing and functional analyses in a large French ADH family and concludes that APOE p.Leu167del is associated with ADH. It does not report the claimed analysis of large Italian families; its additional screened groups were French and Norwegian. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Within a Norwegian hyperlipidemic cohort, APOE p.Arg235Trp (Arg217Trp) was found in a 56-year-old man with total cholesterol, triglyceride, LDL, and HDL levels of 363, 239, 247, and 69.6 mg/dL, respectively, along with the apoE3/E4 isoforms.

    “Within a Norwegian hyperlipidemic cohort, APOE p.Arg235Trp (Arg217Trp) was found in a 56-year-old man with total cholesterol, triglyceride, LDL, and HDL levels of 363, 239, 247, and 69.6 mg/dL, respectively, along with the apoE3/E4 isoforms29).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]

  • Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes.

    “Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes27, 29-40).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]

    The Abstract describes an APOE mutation in a family with autosomal dominant hypercholesterolemia, but does not give a count of APOE-deficiency cases or classify 11 cases by zygosity. Searches for APOE deficiency, homozygotes, and compound heterozygotes found no passage supporting the four-versus-seven breakdown. Page numbers are unavailable in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cenarro study is cited with two different years

    Minor

    The text cites the 8q24.22 locus study as published in 2011, but the matching reference lists its publication year as 2010.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Mahley, 1989, The metabolic basis of inherited diseases, 1195

Cited by

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Related

Authors
Marduel, M., Ouguerram, K., Serre, V., Bonnefont-Rousselot, D., Marques-Pinheiro, A., Erik Berge, K., Devillers, M., Luc, G., Lecerf, J.-M., Tosolini, L., Erlich, D., Peloso, G. M., Stitziel, N., Nitchké, P., Jaïs, J.-P., The French Research Network on ADH, Abifadel, M., Kathiresan, S., Leren, T. P., Rabès, J.-P., Boileau, C., & Varret, M.
Affiliations
  • Inserm (FR)
  • Medical Genetics Laboratory; Oslo University Hospital Rikshospitalet; Oslo; Norway
  • Université de Lille (FR)
  • Centre Hospitalier Universitaire de Lille (FR)
  • Université Paris Denis Diderot; Paris; France
  • Broad Institute (US)
  • Hôpital Necker-Enfants Malades (FR)
  • Oslo University Hospital (NO)
Corresponding author
Varret, Mathilde
ORCID
Venue
Human Mutation
Publisher
Wiley
Published
2012-10-11
Volume
34
Issue
1
Pages
83-87
ISSN
1059-7794 (ISSN-L)
DOI
10.1002/humu.22215
PMC
PMC3638718
OpenAlex
W2072770085
Semantic Scholar
e4d31a1313c36bcd4d0998701fcdf0156fa0f973
Cited by
133
References
32
Citations by year
2026: 7 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 6 · 2019: 9 · 2018: 12 · 2017: 12 · 2016: 9 · 2015: 7 · 2014: 14 · 2013: 10 · 2012: 1
FWCI
10.45
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1055 d)
Locations
  • Human Mutation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Agence Nationale de la Recherche (ANR-05-PCOD-0017, ANR-08-GENO-0002, ANR-06-MRAR-0038)
  • National Heart, Lung, and Blood Institute (R01HL107816)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
autosomal dominant hypercholesterolemia, apolipoprotein E, familial hypercholesterolemia, LDL receptor, apolipoprotein B, PCSK9, type III hyperlipoproteinemia, LDL catabolism, family studies, exome sequencing, genome-wide mapping
MeSH terms
Adolescent, Adult, Apolipoproteins E, Child, Cholesterol, Chromosomes, Human, Pair 19, Family Health, Female, Haplotypes, Humans, Hyperlipoproteinemia Type II, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Models, Molecular, Mutation, Pedigree, Triglycerides, Gene Deletion, Protein Structure, Secondary, Protein Structure, Tertiary, Genetic Predisposition to Disease, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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