Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb
Reference Assembly: GRCh37/hg19
Position: Chr19:45409044 C>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs750782549
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 1, 5' UTR

Findings

This variant, located in the APOE promoter and in the 5' untranslated region of APOE mRNA, was identified in three French patients in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). Two of the carriers had elevated levels of triglycerides in blood and were diagnosed with familial combined hyperlipidemia, also known as hyperlipoproteinemia type IIb (HLPP2b). One had a family history of the disease. The other’s condition was predicted to be caused by multiple genes: the weighted polygenic risk score was in decile 10, indicating a strong probability of polygenic hypercholesterolemia. The third carrier had elevated low-density lipoprotein (LDL) cholesterol in blood and xanthelasma—lipid deposits beneath the skin on or near the eyelids—and was diagnosed with autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a).

None of the carriers had mutations in LDLR, PCSK9, or APOB, the genes most commonly associated with HLPP2a. Moreover, all three had an APOE3/E4 genotype.

Interestingly, the frequency of the variant in the cohort(0.00026) was greater than in the gnomAD variant database (0.00001, gnomAD v3.1.1, Nov 2021). The authors also noted the cohort frequency was higher than that of the gnomAD African/African American population which had the highest frequency in gnomAD (0.000024, including a single heterozygote in a 41,416 allele count). The elevated frequency in a group of affected individuals prompted the authors to classify it as “a variant of uncertain significance/likely pathogenic.”

Biological Effect

The biological effect of this variant is unknown, but it is in the APOE promoter (Paik et al., 1988) within the HuB functional domain (-101 to -15) which was identified as a positive regulatory element and possibly forming part of the core promoter site for transcription initiation (Maloney et al., 2007).

This variant's PHRED-scaled CADD score was 14.9 predicted to be among the top 10 percent of the most deleterious substitutions in the human genome (Abou Khalil et al., 2022). Note that some classifications use 20 as a threshold score (corresponding to the top 1 percent) for predicting a damaging effect. The Mutation Taster algorithm predicted the variant is disease-causing.

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References

Paper Citations

1. Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, Varret M. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci. 2022 May 21;23(10) PubMed.
2. Paik YK, Chang DJ, Reardon CA, Walker MD, Taxman E, Taylor JM. Identification and characterization of transcriptional regulatory regions associated with expression of the human apolipoprotein E gene. J Biol Chem. 1988 Sep 15;263(26):13340-9. PubMed.
3. Maloney B, Ge YW, Alley GM, Lahiri DK. Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.

Further Reading

No Available Further Reading