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Familial hypercholesterolemia 1(FHCL1)

MedGen UID:
152875
Concept ID:
C0745103
Disease or Syndrome
Synonyms: FHCL1; Fredrickson type IIa hyperlipoproteinemia; Hyper-beta-lipoproteinemia; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF; HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL; Hyperlipoproteinemia type 2; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type IIa; LDL RECEPTOR DISORDER; LDLR-Related Familial Hypercholesterolemia, Autosomal Dominant
SNOMED CT: Fredrickson type IIa hyperlipoproteinemia (397915002)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Genes (locations): APOA2 (1q23.3); EPHX2 (8p21.2-21.1); GHR (5p13.1-12); LDLR (19p13.2); PPP1R17 (7p14.3)
 
Monarch Initiative: MONDO:0007750
OMIM®: 143890

Disease characteristics

Excerpted from the GeneReview: Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or nonfatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years. An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years. In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common. [from GeneReviews]
Authors:
Emily Youngblom  |  Mitchel Pariani  |  Joshua W Knowles   view full author information

Additional description

From OMIM
Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (Hobbs et al., 1992). The FHCL1 phenotype can be modified by mutation in other genes. For example, in individuals with the LDLR mutation IVS14+1G-A (606945.0063), the phenotype can be altered by a SNP in the APOA2 gene (107670.0002), a SNP in the EPHX2 gene (132811.0001), or a SNP in the GHR gene (600946.0028). Genetic Heterogeneity of Familial Hypercholesterolemia Other forms of monogenic familial hypercholesterolemia include FHCL2 (144010), caused by mutation in the APOB gene (107730); FHCL3 (603776), caused by mutation in the PCSK9 gene (607786); and FHCL4 (603813), caused by mutation in the LDLRAP1 gene (605747).  http://www.omim.org/entry/143890

Clinical features

From HPO
Coronary artery disease
MedGen UID:
365486
Concept ID:
C1956346
Disease or Syndrome
Reduction of the diameter of the coronary arteries as the result of an accumulation of atheromatous plaques within the walls of the coronary arteries, which increases the risk of myocardial ischemia.
Tendon xanthomatosis
MedGen UID:
450999
Concept ID:
C0221253
Disease or Syndrome
The presence of xanthomas (intra-and extra-cellular accumulations of cholesterol) extensor tendons (typically over knuckles, Achilles tendon, knee, and elbows).
Increased circulating low-density lipoprotein levels
MedGen UID:
154289
Concept ID:
C0549399
Finding
An elevated concentration of low-density lipoprotein cholesterol in the blood.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Tendon xanthomatosis
MedGen UID:
450999
Concept ID:
C0221253
Disease or Syndrome
The presence of xanthomas (intra-and extra-cellular accumulations of cholesterol) extensor tendons (typically over knuckles, Achilles tendon, knee, and elbows).
Arcus senilis
MedGen UID:
8179
Concept ID:
C0003742
Finding
A corneal disease in which there is a deposition of phospholipid and cholesterol in the corneal stroma and anterior sclera.

Professional guidelines

PubMed

Feldman DI, Blaha MJ, Santos RD, Jones SR, Blumenthal RS, Toth PP, Sperling LS, Martin SS
Curr Atheroscler Rep 2015 Jan;17(1):473. doi: 10.1007/s11883-014-0473-6. PMID: 25404096
ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjærg-Hansen A, Watts GF, Averna M, Boileau C, Borén J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ; European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia.
Eur Heart J 2014 Aug 21;35(32):2146-57. Epub 2014 Jul 22 doi: 10.1093/eurheartj/ehu274. PMID: 25053660Free PMC Article
Myśliwiec M, Walczak M, Małecka-Tendera E, Dobrzańska A, Cybulska B, Filipiak K, Mazur A, Jarosz-Chobot P, Szadkowska A, Rynkiewicz A, Chybicka A, Socha P, Brandt A, Bautembach-Minkowska J, Zdrojewski T, Limon J, Gidding SS, Banach M
J Clin Lipidol 2014 Mar-Apr;8(2):173-80. Epub 2014 Jan 18 doi: 10.1016/j.jacl.2014.01.001. PMID: 24636176
Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ
Int J Cardiol 2014 Feb 15;171(3):309-25. Epub 2013 Nov 20 doi: 10.1016/j.ijcard.2013.11.025. PMID: 24418289
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article
Rynkiewicz A, Cybulska B, Banach M, Filipiak K, Guzik T, Idzior-Waluś B, Imiela J, Jankowski P, Kłosiewicz-Latoszek L, Limon J, Myśliwiec M, Opolski G, Steciwko A, Stępińska J, Zdrojewski T
J Clin Lipidol 2013 May-Jun;7(3):217-21. Epub 2013 Feb 4 doi: 10.1016/j.jacl.2013.01.005. PMID: 23725921
Sullivan DR, Hamilton-Craig I, van Bockxmeer F, Watts GF; CSANZ Cardiac Genetics Diseases Council Writing Group.
Heart Lung Circ 2012 Mar;21(3):159-62. Epub 2012 Jan 30 doi: 10.1016/j.hlc.2011.11.006. PMID: 22364837
Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE; National Lipid Association Expert Panel on Familial Hypercholesterolemia.
J Clin Lipidol 2011 Jun;5(3 Suppl):S1-8. Epub 2011 Apr 12 doi: 10.1016/j.jacl.2011.04.003. PMID: 21600525
Civeira F; International Panel on Management of Familial Hypercholesterolemia.
Atherosclerosis 2004 Mar;173(1):55-68. doi: 10.1016/j.atherosclerosis.2003.11.010. PMID: 15177124

External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Identification and management of familial hypercholesterolaemia

ACMG SF v3.0, 2021

Recent clinical studies

Etiology

Barkas F, Nomikos T, Liberopoulos E, Panagiotakos D
Nutrients 2020 Aug 13;12(8) doi: 10.3390/nu12082436. PMID: 32823643Free PMC Article
Climent E, Pérez-Calahorra S, Benaiges D, Pintó X, Suárez-Tembra M, Plana N, Sánchez-Hernández RM, Valdivielso P, Ascaso JF, Pedro-Botet J
Rev Esp Cardiol (Engl Ed) 2020 Sep;73(9):718-724. Epub 2019 Oct 28 doi: 10.1016/j.rec.2019.09.001. PMID: 31672559
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U
Cochrane Database Syst Rev 2019 Nov 7;2019(11) doi: 10.1002/14651858.CD006401.pub5. PMID: 31696945Free PMC Article
Patel P, Hu Y, Kolinovsky A, Geng Z, Ruhl J, Krishnamurthy S, deRichemond C, Khan A, Kirchner HL, Metpally R, Jones LK, Sturm AC, Carey D, Snyder S, Williams MS, Mehra VC
J Am Heart Assoc 2019 Jul 2;8(13):e011822. Epub 2019 Jun 29 doi: 10.1161/JAHA.118.011822. PMID: 31256702Free PMC Article
Hagger MS, Hardcastle SJ, Hu M, Kwok S, Lin J, Nawawi HM, Pang J, Santos RD, Soran H, Su TC, Tomlinson B, Watts GF
Eur J Prev Cardiol 2018 Jun;25(9):936-943. Epub 2018 Mar 29 doi: 10.1177/2047487318766954. PMID: 29592531

Diagnosis

Representatives of the Global Familial Hypercholesterolemia Community., Wilemon KA, Patel J, Aguilar-Salinas C, Ahmed CD, Alkhnifsawi M, Almahmeed W, Alonso R, Al-Rasadi K, Badimon L, Bernal LM, Bogsrud MP, Braun LT, Brunham L, Catapano AL, Cillíková K, Corral P, Cuevas R, Defesche JC, Descamps OS, de Ferranti S, Eiselé JL, Elikir G, Folco E, Freiberger T, Fuggetta F, Gaspar IM, Gesztes ÁG, Grošelj U, Hamilton-Craig I, Hanauer-Mader G, Harada-Shiba M, Hastings G, Hovingh GK, Izar MC, Jamison A, Karlsson GN, Kayikçioglu M, Koob S, Koseki M, Lane S, Lima-Martinez MM, López G, Martinez TL, Marais D, Marion L, Mata P, Maurina I, Maxwell D, Mehta R, Mensah GA, Miserez AR, Neely D, Nicholls SJ, Nohara A, Nordestgaard BG, Ose L, Pallidis A, Pang J, Payne J, Peterson AL, Popescu MP, Puri R, Ray KK, Reda A, Sampietro T, Santos RD, Schalkers I, Schreier L, Shapiro MD, Sijbrands E, Soffer D, Stefanutti C, Stoll M, Sy RG, Tamayo ML, Tilney MK, Tokgözoglu L, Tomlinson B, Vallejo-Vaz AJ, Vazquez-Cárdenas A, de Luca PV, Wald DS, Watts GF, Wenger NK, Wolf M, Wood D, Zegerius A, Gaziano TA, Gidding SS
JAMA Cardiol 2020 Feb 1;5(2):217-229. doi: 10.1001/jamacardio.2019.5173. PMID: 31895433
Climent E, Pérez-Calahorra S, Benaiges D, Pintó X, Suárez-Tembra M, Plana N, Sánchez-Hernández RM, Valdivielso P, Ascaso JF, Pedro-Botet J
Rev Esp Cardiol (Engl Ed) 2020 Sep;73(9):718-724. Epub 2019 Oct 28 doi: 10.1016/j.rec.2019.09.001. PMID: 31672559
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U
Cochrane Database Syst Rev 2019 Nov 7;2019(11) doi: 10.1002/14651858.CD006401.pub5. PMID: 31696945Free PMC Article
Aljenedil S, Ruel I, Watters K, Genest J
J Clin Lipidol 2018 Jul - Aug;12(4):872-877. Epub 2018 Apr 3 doi: 10.1016/j.jacl.2018.03.087. PMID: 29778561
Hagger MS, Hardcastle SJ, Hu M, Kwok S, Lin J, Nawawi HM, Pang J, Santos RD, Soran H, Su TC, Tomlinson B, Watts GF
Eur J Prev Cardiol 2018 Jun;25(9):936-943. Epub 2018 Mar 29 doi: 10.1177/2047487318766954. PMID: 29592531

Therapy

Barkas F, Nomikos T, Liberopoulos E, Panagiotakos D
Nutrients 2020 Aug 13;12(8) doi: 10.3390/nu12082436. PMID: 32823643Free PMC Article
Di Minno MND, Gentile M, Di Minno A, Iannuzzo G, Calcaterra I, Buonaiuto A, Di Taranto MD, Giacobbe C, Fortunato G, Rubba POF
Nutr Metab Cardiovasc Dis 2020 Jun 9;30(6):996-1004. Epub 2020 Mar 6 doi: 10.1016/j.numecd.2020.02.018. PMID: 32402582
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U
Cochrane Database Syst Rev 2019 Nov 7;2019(11) doi: 10.1002/14651858.CD006401.pub5. PMID: 31696945Free PMC Article
Rizos CV, Elisaf MS, Skoumas I, Tziomalos K, Kotsis V, Rallidis L, Garoufi A, Athyros VG, Skalidis E, Kolovou G, Koutagiar I, Papagianni M, Antza C, Katsiki N, Ganotakis E, Liberopoulos EN
Atherosclerosis 2018 Oct;277:308-313. doi: 10.1016/j.atherosclerosis.2018.08.017. PMID: 30270064
Aljenedil S, Ruel I, Watters K, Genest J
J Clin Lipidol 2018 Jul - Aug;12(4):872-877. Epub 2018 Apr 3 doi: 10.1016/j.jacl.2018.03.087. PMID: 29778561

Prognosis

Climent E, Pérez-Calahorra S, Benaiges D, Pintó X, Suárez-Tembra M, Plana N, Sánchez-Hernández RM, Valdivielso P, Ascaso JF, Pedro-Botet J
Rev Esp Cardiol (Engl Ed) 2020 Sep;73(9):718-724. Epub 2019 Oct 28 doi: 10.1016/j.rec.2019.09.001. PMID: 31672559
Patel P, Hu Y, Kolinovsky A, Geng Z, Ruhl J, Krishnamurthy S, deRichemond C, Khan A, Kirchner HL, Metpally R, Jones LK, Sturm AC, Carey D, Snyder S, Williams MS, Mehra VC
J Am Heart Assoc 2019 Jul 2;8(13):e011822. Epub 2019 Jun 29 doi: 10.1161/JAHA.118.011822. PMID: 31256702Free PMC Article
Hagger MS, Hardcastle SJ, Hu M, Kwok S, Lin J, Nawawi HM, Pang J, Santos RD, Soran H, Su TC, Tomlinson B, Watts GF
Eur J Prev Cardiol 2018 Jun;25(9):936-943. Epub 2018 Mar 29 doi: 10.1177/2047487318766954. PMID: 29592531
Zafrir B, Jubran A, Lavie G, Halon DA, Flugelman MY, Shapira C
Eur J Prev Cardiol 2017 May;24(8):867-875. Epub 2017 Feb 10 doi: 10.1177/2047487317693132. PMID: 28186442
Mundal L, Igland J, Ose L, Holven KB, Veierød MB, Leren TP, Retterstøl K
Eur J Prev Cardiol 2017 Jan;24(2):137-144. Epub 2016 Oct 28 doi: 10.1177/2047487316676135. PMID: 27794106

Clinical prediction guides

Di Minno MND, Gentile M, Di Minno A, Iannuzzo G, Calcaterra I, Buonaiuto A, Di Taranto MD, Giacobbe C, Fortunato G, Rubba POF
Nutr Metab Cardiovasc Dis 2020 Jun 9;30(6):996-1004. Epub 2020 Mar 6 doi: 10.1016/j.numecd.2020.02.018. PMID: 32402582
Representatives of the Global Familial Hypercholesterolemia Community., Wilemon KA, Patel J, Aguilar-Salinas C, Ahmed CD, Alkhnifsawi M, Almahmeed W, Alonso R, Al-Rasadi K, Badimon L, Bernal LM, Bogsrud MP, Braun LT, Brunham L, Catapano AL, Cillíková K, Corral P, Cuevas R, Defesche JC, Descamps OS, de Ferranti S, Eiselé JL, Elikir G, Folco E, Freiberger T, Fuggetta F, Gaspar IM, Gesztes ÁG, Grošelj U, Hamilton-Craig I, Hanauer-Mader G, Harada-Shiba M, Hastings G, Hovingh GK, Izar MC, Jamison A, Karlsson GN, Kayikçioglu M, Koob S, Koseki M, Lane S, Lima-Martinez MM, López G, Martinez TL, Marais D, Marion L, Mata P, Maurina I, Maxwell D, Mehta R, Mensah GA, Miserez AR, Neely D, Nicholls SJ, Nohara A, Nordestgaard BG, Ose L, Pallidis A, Pang J, Payne J, Peterson AL, Popescu MP, Puri R, Ray KK, Reda A, Sampietro T, Santos RD, Schalkers I, Schreier L, Shapiro MD, Sijbrands E, Soffer D, Stefanutti C, Stoll M, Sy RG, Tamayo ML, Tilney MK, Tokgözoglu L, Tomlinson B, Vallejo-Vaz AJ, Vazquez-Cárdenas A, de Luca PV, Wald DS, Watts GF, Wenger NK, Wolf M, Wood D, Zegerius A, Gaziano TA, Gidding SS
JAMA Cardiol 2020 Feb 1;5(2):217-229. doi: 10.1001/jamacardio.2019.5173. PMID: 31895433
Climent E, Pérez-Calahorra S, Benaiges D, Pintó X, Suárez-Tembra M, Plana N, Sánchez-Hernández RM, Valdivielso P, Ascaso JF, Pedro-Botet J
Rev Esp Cardiol (Engl Ed) 2020 Sep;73(9):718-724. Epub 2019 Oct 28 doi: 10.1016/j.rec.2019.09.001. PMID: 31672559
Patel P, Hu Y, Kolinovsky A, Geng Z, Ruhl J, Krishnamurthy S, deRichemond C, Khan A, Kirchner HL, Metpally R, Jones LK, Sturm AC, Carey D, Snyder S, Williams MS, Mehra VC
J Am Heart Assoc 2019 Jul 2;8(13):e011822. Epub 2019 Jun 29 doi: 10.1161/JAHA.118.011822. PMID: 31256702Free PMC Article
Hagger MS, Hardcastle SJ, Hu M, Kwok S, Lin J, Nawawi HM, Pang J, Santos RD, Soran H, Su TC, Tomlinson B, Watts GF
Eur J Prev Cardiol 2018 Jun;25(9):936-943. Epub 2018 Mar 29 doi: 10.1177/2047487318766954. PMID: 29592531

Recent systematic reviews

Barkas F, Nomikos T, Liberopoulos E, Panagiotakos D
Nutrients 2020 Aug 13;12(8) doi: 10.3390/nu12082436. PMID: 32823643Free PMC Article
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U
Cochrane Database Syst Rev 2019 Nov 7;2019(11) doi: 10.1002/14651858.CD006401.pub5. PMID: 31696945Free PMC Article
Lee C, Rivera-Valerio M, Bangash H, Prokop L, Kullo IJ
Circ Genom Precis Med 2019 Nov;12(11):e002723. Epub 2019 Oct 22 doi: 10.1161/CIRCGEN.119.002723. PMID: 31638829
Lee S, Akioyamen LE, Aljenedil S, Rivière JB, Ruel I, Genest J
Eur J Prev Cardiol 2019 Aug;26(12):1262-1270. Epub 2019 Feb 12 doi: 10.1177/2047487319829746. PMID: 30755017
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U
Cochrane Database Syst Rev 2017 Jul 7;7:CD006401. doi: 10.1002/14651858.CD006401.pub4. PMID: 28685504Free PMC Article

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