Familial hypercholesterolaemia
Gene: APOE
PMID: 27014949- The leu167del variant has also been associated with hypercholesterolaemia, it only has 3 hets 0 homs in v2. It has been seen to segregate in several families with autosomal dominant hypercholesterolemia.
PMID: 34058468 also lists many more variants have been previously reported and associated with a range of dyslipoproteinemias in table 1. Arg163Cys was seen to segregate in a het mother with raised LDL cholesterol and in her homozygote son who had even higher LDL cholesterol. Leu167del and 2 other missense variant have also been seen to segregate in families with familial combined hyperlipidemia.
There is also a lot of talk in the literature about the 3 main alleles of APOE- E3 is wild type with Cys130 (previously 112) and Arg176 (previously 158) (PMID: 33679311).
The E2 allele (with the Arg176Cys variant) has been associated with hyperlipoproteinemia, type III when homozygous, but it seems to be essentially only a risk factor and only causes disease in the presence of other environmental/genetic risk factors (PMID: 34058468). E2 is also a protective factor against Alzheimer’s.
E4 is a risk factor for alzhiemers disease and has the Cys130Arg variant, it is also associated with increased LDL cholesterol levels and thus associated with cardiovascular disease risk (PMID: 34058468).
However it is worth noting that the Arg176Cys variant has 10,066 hets and 465 homs in gnomad v2, and Cys130Arg has 24,455 hets and 2091 homs.
Therefore it seems like there are some risk factor variant in APOE that are very high in the population, but also some genuine variants with reasonable population counts that are associated with a range of hypercholesterolaemias/dyslipoproteinemias.Created: 30 Mar 2022, 10:23 p.m. | Last Modified: 30 Mar 2022, 10:24 p.m.
Panel Version: 0.22
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
Hyperlipoproteinemia, type III (MIM#617347); Sea-blue histiocyte disease (MIM#269600)
Publications
Gene: apoe has been classified as Green List (High Evidence).
Phenotypes for gene: APOE were changed from to Hyperlipoproteinemia, type III (MIM#617347); Sea-blue histiocyte disease (MIM#269600)
Publications for gene: APOE were set to
Mode of inheritance for gene: APOE was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
gene: APOE was added gene: APOE was added to Familial hypercholesterolaemia_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: APOE was set to Unknown