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Familial hypercholesterolemia

From SNPedia

Individuals with Familial hypercholesterolemia (FH) have abnormally elevated LDL-C levels, often 2 - 3 fold higher than normal. FH can be inherited in a Mendelian fashion in either in an autosomal dominant manner (Autosomal Dominant Hypercholesterolemia) or an autosomal recessive manner (Autosomal Recessive Hypercholesterolemia). The prevalence of the heterozygous form of FH is now thought to be about 1 in 250 individuals, and given the >20x fold higher risk for coronary disease that such carriers have, treatment options starting at an early age should be considered.[PMID 17483372],[PMID 28652387OA-icon.png]

Autosomal Dominant Hypercholesterolemia (ADH) can be caused by a mutation in the LDLR, APOB and PCSK9 genes; whereas Autosomal Recessive Hypercholesterolemia (ARH) is caused by homozygous mutations in either the LDLR or Autosomal Recessive Hypercholesterolemia LDLRAP1 genes. The autosomal dominant form of FH is much more common than the autosomal recessive form of FH. The frequency of FH due to LDLR, APOB, PCSK9 and ARH mutations is 52%-76%, 2-10%, 2% and 2%, respectively. Therefore, SNPs in the LDLR gene are by far the most common cause of heterozygous FH.[PMID 17483372]

Familial hypercholesterolemia has a ClinGen Actionability summary for pathogenic variants in the LDLR, APOB and PCSK9 genes.

These OMIM entries discuss three forms of FH, and give some alternative symbols and acronyms, useful to know:

  • OMIM_143890, Autosomal dominant hypercholesterolemia
  • OMIM_144010, Autosomal dominant hypercholesterolemia, type B
  • OMIM_603813, Autosomal recessive hypercholesterolemia

For example, in Finland, seven different mutations of the LDL receptor gene LDLR are FH-Helsinki (large deletion), FH-North Karelia (small deletion), FH-Turku (G823D), FH-Pori (L380H), FH-Pogosta (R574Q), FH-Fin11 (D558N), and FH-Fin12 (C331W). These mutations are responsible for approximately 93% of all FH cases in Finland; further discussion can be found in Mia Koskinenː Studies in children with heterozygous familial hypercholesterolemia and in pediatric cardiac transplant recipients, doctoral dissertation, University of Helsinki, 2006.


GWAS and whole exome sequencing studies related to FH[edit]

[PMID 26077743OA-icon.png] Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing.

[PMID 24916650OA-icon.png] Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

[PMID 23054246OA-icon.png] Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia.

Other publications[edit]

[PMID 26755827OA-icon.png] Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia.

[PMID 27084339OA-icon.png] The genetics and screening of familial hypercholesterolaemia.

[PMID 26908947] Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.

[PMID 26836380] 'Lithuanian' Mutation Finally Found in Lithuania.

[PMID 26077743OA-icon.png] Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing.

[PMID 25911074] Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry.

[PMID 25712136OA-icon.png] Genetics of familial hypercholesterolemia.

[PMID 25670911OA-icon.png] The genetics of familial hypercholesterolemia and emerging therapies.

[PMID 25458642OA-icon.png] Reducing the burden of disease and death from familial hypercholesterolemia: A call to action

[PMID 25437892] Prevalence and clinical correlates of familial hypercholesterolemia founder mutations in the general population. - The article includesː "Five LDLR founder mutations, FH-North Karelia, FH-Helsinki, FH-Pogosta, FH-Turku, and FH-Pori, were genotyped."

[PMID 25395270] Hierarchical Bayesian model for rare variant association analysis integrating genotype uncertainty in human sequence data.

[PMID 25278210OA-icon.png] rs11613352 polymorphism (TT genotype) associates with a decrease of triglycerides and an increase of HDL in familial hypercholesterolemia patients.

[PMID 25231171OA-icon.png] Transmission of LDLR mutation from donor through liver transplantation resulting in hypercholesterolemia in the recipient.

[PMID 24987033OA-icon.png] Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

[PMID 24956927OA-icon.png] Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.

[PMID 24785115OA-icon.png] Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing. {{PMID Auto |PMID=24585268 |Title=Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. |OA=0

[PMID 24529147OA-icon.png] Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.

[PMID 24404629OA-icon.png] Familial Hypercholesterolemia.

[PMID 24373485OA-icon.png] Familial hypercholesterolemia mutations in Petrozavodsk: no similarity to St. Petersburg mutation spectrum.

[PMID 24137609] "Finnish" mutations in LDL receptor gene: a rare cause of familial hypercholesterolemia in St. Petersburg and Petrozavodsk.

[PMID 21657943] Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution.

[PMID 12052488] Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene.

[PMID 11585102] Familial hypercholesterolaemia in Finland: common, rare and mild mutations of the LDL receptor and their clinical consequences. Finnish FH-group.

[PMID 9409302OA-icon.png] Familial hypercholesterolemia in the Finnish North Karelia. A molecular, clinical, and genealogical study.

[PMID 7573037OA-icon.png] Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene.

[PMID 2760198OA-icon.png] Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.

[PMID 1372927] Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland.

[PMID 1634609OA-icon.png] The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland.