Familial Hypercholesterolemia Genetic Testing

Lab Management Guidelines v2.0.2019 Familial Hypercholesterolemia Genetic Testing

MOL.TS.169.A v2.0.2019 Procedures addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.

Procedures addressed by this Procedure codes guideline LDLR Known Familial Mutation 81403 APOB Known Familial Mutation 81403 PCSK9 Known Familial Mutation 81403 LDLR Sequencing 81406 LDLR Deletion/Duplication 81405 APOB Targeted Mutation Analysis 81401 APOB Sequencing 81479 PCSK9 Sequencing 81406

What is familial hypercholesterolemia

Definition

Familial hypercholesterolemia (FH) is a genetic disorder characterized by very high levels of low-density lipoprotein (LDL) cholesterol.  Familial hypercholesterolemia (FH) is a genetic disorder characterized by very high levels of low-density lipoprotein (LDL) cholesterol: usually >190 mg/dL in untreated adults. This leads to an increased risk for coronary heart disease (CHD), including heart attacks, at an early age.1,2,3 o Men with untreated FH have a 50% risk for a coronary event by age 50.3,4 o Women with untreated FH have a 30% risk for a coronary event by age 60.3,4  People with untreated FH have about a 20 fold increase for coronary heart disease.3  Early and aggressive LDL-lowering with high doses of potent statins or statin combination therapy significantly lowers CHD morbidity and mortality for people

with FH.5,6 Statins are contraindicated during pregnancy due to concerns for teratogenicity and should be discontinued prior to conception.3 Because there is considerable overlap between the LDL levels of those with FH and common multifactorial hypercholesterolemia, FH often goes undiagnosed until middle age, when much of the preventive value of cholesterol-lowering therapy is lost.7  For FH patients who are not adequately controlled with statin therapy, or with intolerance to statins, PCSK9 inhibitors (e.g evolocumab, alirocumab) may be an effective alternative treatment.8  Less than 10% of people with FH are adequately treated.9  Various criteria for identifying FH clinically have been developed and are described below:4

Diagnosis: MEDPED criteria

MEDPED criteria4 Total Cholesterol (LDL), mg/dL

Patient’s age Patient has 1st Patient has 2nd Patient has 3rd General degree relative degree relative degree relative population with FH with FH with FH a

<18 220 (155) 230 (165) 240 (170) 270 (200) i

20 240 (170) 250 (180) 260 (185) 290 (220) m e

30 270 (190) 280 (200) 290 (210) 340 (240) l

40+ 290 (205) 300 (215) 310 (225) 360 (260) o r e Diagnosis: Dutch criteria t s

4 e

Definitive FH: 8 points or more; Probable FH: 6-7 points; Possible FH: 3-5 points l o Points Description h

1 point First-degree relative with premature c cardiovascular disease or LDL >95th r percentile, or personal history of e premature peripheral or cerebrovascular p disease or LDL 155-189 mg/dL** y H

2 points First-degree relative with tendinous xanthoma or corneal arcus, or first-degree l a

relative age <18 with LDL >95th i l

percentile, or personal history of coronary i artery disease m ** 3 points LDL 190-249 mg/dL a F

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Lab Management Guidelines v2.0.2019

Points Description 4 points Corneal arcus in patient age <45 years 5 points LDL 250-329 mg/dL** 6 points Tendon xanthoma 8 points LDL ≥330 mg/dL**

Note ** Please note that these are LDL level cut offs for untreated individuals.

Diagnosis: Simon Broome criteria

Definitive FH  Total cholesterol (LDL): 290 (190) mg/dL in adults or 260 (155) mg/dL in pediatric patients and:  DNA mutation

Probable FH  Total cholesterol (LDL): 290 (190) mg/dL in adults or 260 (155) mg/dL in pediatric patients and: a i  Tendon xanthoma in patient or in first-or second-degree relative m

Possible FH e l

 Total cholesterol (LDL): 290 (190) mg/dL in adults or 260 (155) mg/dL in pediatric o patients and: r e  Family history of myocardial infarction (MI) at age <50 in second-degree relative or t at age <60 in first-degree relative or family history of total cholesterol >290 mg/dL in s e

first- or second-degree relative l o

Prevalence h c

About 1 in 200-250 people worldwide have FH.3 The risk is much higher in some South r African Afrikaner, Amish, Lebanese, and Finnish populations.3 e p

Approximately 1 in 300 to 500 people have heterozygous FH, which means they have y one copy of the gene mutation. H

Approximately one in 1 million people have homozygous FH, which means they have 2 l copies of the gene mutation. This is much more severe than heterozygous FH.4 People a i l

with this type of FH typically have severe coronary heart disease by their mid-20s; the i rate of death or the need for surgical treatment of heart problems by the teenage years is high.3 m a F

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Lab Management Guidelines v2.0.2019

Cause

Most cases of FH are caused by mutations in one of three genes: LDLR, APOB, PCSK9.3 However, mutations in these genes only account for approximately 60%-80% of FH.3 There are likely other genes that are not known at the present time that make up the remaining 20%-40% of cases of FH. Therefore, a negative genetic test does not rule out a diagnosis of FH.

Inheritance

FH is an autosomal dominant condition, meaning that only one gene mutation is needed to cause the condition. A person with heterozygous FH has a 50% chance to pass the mutation to each child. Although not included in this guideline, it is important to note that there is an autosomal recessive form of hypercholesterolemia which is caused by mutations in the LDLRAP1 gene. There is also a milder autosomal dominant form, Familial Combined Hyperlipidemia, which is usually caused by mutations in the LPL gene.3

Test information a  A clinical diagnosis of FH is suspected based on some combination of personal and i

family history of very high cholesterol, premature CHD, and cholesterol deposits, m 2

such as tendon xanthomas and corneal arcus. At least three organizations have e attempted to define clinical diagnostic criteria for FH, but all criteria have recognized l limitations.10 The three different criteria are described above. o r

 Genetic testing for FH can confirm a diagnosis of FH, particularly in borderline e t clinical cases.9,11,12 s

 Laboratories may offer evaluation of the LDLR, APOB, or PCSK9 genes e l individually, as panels, or with reflex options. o

o LDLR: Over 1000 mutations have been characterized so sequence analysis is h required. Major gene deletions and rearrangements account for an estimated c r 9% of LDLR mutations and require specialized deletion testing to detect them.13 e

o APOB: FH-causing APOB mutations are primarily found in a limited region of p 13 the gene, with the R3500Q mutation being most common. Laboratory testing y

may be done by targeted mutation analysis for a limited number of APOB H

mutations or sequencing of the gene region where these mutations are l 3 generally found. According to GeneReviews, as of 2016 there has been only a 3 i one reported case of a deletion in APOB causing FH. l i o PCSK9: “Gain of function mutations in PCSK9 cause fewer than 5% of cases in most studies.” 14 According to GeneReviews, as of 2016 there have been no m deletions or duplications reported in PCSK9 that cause FH.3 a F

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Lab Management Guidelines v2.0.2019

 Once a mutation is found in an affected person, single-site testing should be offered to at-risk family members to allow for appropriately early intervention.15,16

Genetic testing for FH

Proportion of FH attributed to each gene. Molecular Genetic Testing for FH

Gene Proportion of FH Test Method3 Attributed to Mutations in Gene3 LDLR 60%-80% Sequence Analysis Deletion/Duplication

APOB 1%-5% Targeted Analysis Sequencing Analysis Deletion/Duplication

PCSK9 0%-3% Targeted Analysis Sequencing Analysis

Deletion/Duplication a i

Unknown 20%-40% NA m e l o

Guidelines and evidence r e Guidelines and evidence - genetic testing t s e

 Evidence-based guidelines by the National Institute for Clinical Excellence of UK l

(NICE, 2008 (reaffirmed 2016)) support genetic testing for FH as follows:16 o h

o “A diagnosis of FH should be made using the Simon Broome criteria, which c

include a combination of family history, clinical signs (specifically tendon r xanthomata), cholesterol concentration and DNA testing (see appendix E of the e

NICE guideline).” p y o “Healthcare professionals should offer people with a clinical diagnosis of FH a H

DNA test to increase the certainty of their diagnosis and to aid diagnosis among their relatives.” l a i

o “Healthcare professionals should inform all people who have an identified l mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if i

their LDL-C concentration does not meet the diagnostic criteria (see appendix m

E).” a F

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Lab Management Guidelines v2.0.2019

o “In a family where a DNA mutation is identified, not all family members may have inherited the mutation. When DNA testing has excluded FH in a member of a family, healthcare professionals should manage the person's coronary heart disease risk as in the general population.” o “In families in which a mutation has been identified, the mutation and not LDL-C concentration should be used to identify affected relatives. This should include at least the first- and second- and, when possible, third-degree biological relatives.” o “In children at risk of FH because of one affected parent, the following diagnostic tests should be carried out by the age of 10 years or at the earliest opportunity thereafter. ”

. “A DNA test if the family mutation is known.” . “LDL-C concentration measurement if the family mutation is not known. When excluding a diagnosis of FH a further LDL-C measurement should be repeated after puberty because LDL-C concentrations change during puberty.”  The European Atherosclerosis Society Consensus Panel (2015) states the following:17

o “Given the proven atherogenicity of LDL-C in experimental models and in a humans with FH, with evidence that exposure to even moderate i

hypercholesterolaemia increases the long-term risk of a new CHD event, and m

given the lifelong benefit of genetically determined low LDL-C concentrations, e there is an urgent need to identify and treat FH early to maximize therapeutic l o

benefit…. Detection of a pathogenic mutation, usually in the LDLR gene, is the r

gold standard for diagnosis of FH.” e t  Consensus-based guidelines from The Cardiac Society of Australia and New s

Zealand (CSANZ, 2013) state: “Although the clinical picture of FH will be clear-cut e in many instances, the diagnostic criteria suggest that genetic testing can provide l certainty of diagnosis in some cases where confounding factors such as borderline o

cholesterol levels, inconclusive family histories or tendon injuries have resulted in a h diagnostic dilemma.” 11 c r

 The National Lipid Association expert panel on Familial Hypercholesterolemia e 14 (2011) made the following recommendations regarding genetic testing: p y

o “Genetic screening for FH is generally not needed for diagnosis or clinical H

management but may be useful when the diagnosis is uncertain.” l a

o “Identification of a causal mutation may provide additional motivation for some i l

patients to implement appropriate treatment.” i

o “Importantly, a negative genetic test does not exclude FH, since approximately m

20% of clinically definite FH patients will not be found to have a mutation despite a

an exhaustive search using current methods.” F

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Guidelines and evidence - drug treatment

 The US Food and Drug Administration approved the following PCSK9 inhibitors as treatment for FH. However, there have been no guidelines recommending that genetic testing should be performed for the sole purpose of treatment decisions (i.e. PCSK9 inhibitors) in the absence of a clinical suspicion of FH: o “Praluent (alirocumab) injection in adult patients with heterozygous familial hypercholesterolemia or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL cholesterol.” 18 o “Repatha (evolocumab) injections for use in additional to diet and maximally- tolerated statin therapy in adult patients with heterozygous hypercholesterolemia, homozygous hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require additional lowering of LDL cholesterol.” 19

Criteria

LDLR, APOB, PCSK9 Known Familial Mutation Testing a

 Clinical Consultation: i

o Pre and post-test genetic counseling by an appropriate provider (as deemed by m

the Health Plan policy), AND e l

 Previous Genetic Testing: o r

o No previous genetic testing of LDLR, APOB, or PCSK9, and e t st nd rd o LDLR, APOB, or PCSK9 mutation identified in 1 , 2 or 3 degree biological s

relative, AND e l

 Diagnostic Testing: o h

LDL cholesterol of >120 mg/dL in the absence of treatment c o r e LDLR Full Sequence and Deletion/Duplication Analysis p y  Clinical Consultation: H

o Pre and post-test genetic counseling by an appropriate provider (as deemed by l a

the Health Plan policy), AND i l  Previous Testing: i

o No previous LDLR sequencing or deletion/duplication testing, and m a

o No known LDLR, APOB, or PCSK9 mutation in the family, AND F

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 Diagnostic Testing:

o Member meets the MEDPED criteria or either the Dutch criteria or the Simon Broome criteria for possible or probable FH, and o Genetic testing is necessary because there is uncertainty in the clinical diagnosis

APOB Targeted Mutation Analysis or Full Sequence Analysis

 Criteria for LDLR sequencing and deletion/duplication analysis is met, AND  No previous full sequence analysis of APOB, AND  No mutations detected in full sequencing or deletion/duplication testing of LDLR or PCSK9 sequencing, if previously performed

PCSK9 Full Sequence Analysis

 Criteria for LDLR sequencing and deletion/duplication analysis is met, AND  No previous genetic testing for PCSK9, AND  No mutations detected in full sequencing or deletion/duplication analysis of LDLR or

APOB sequencing, if previously performed a i

LDLR, APOB, PCSK9 Multigene Panels m e l FH multi-gene panels, limited to testing for LDLR, APOB, and PCSK9, will be o reimbursed when the following criteria are met: r e

 Clinical Consultation: t s

o Pre and post-test genetic counseling by an appropriate provider (as deemed by e the Health Plan policy), AND l o

 Previous Testing: h c

o No previous LDLR, APOB, or PCSK9 sequencing or deletion/duplication testing, r

and e

o No known LDLR, APOB, or PCSK9 mutation in the family, AND p y

 Diagnostic Testing: H

o Member meets the MEDPED criteria or either the Dutch criteria or the Simon a i

Broome criteria for possible or probable FH, and l i o Genetic testing is necessary because there is uncertainty in the clinical m diagnosis a F

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Exclusions

Genetic testing for the sole purpose of treatment decisions (i.e. PCSK9 inhibitors) in the absence of a clinical suspicion supported by either the MEDPED, Dutch, or Simon Broome criteria is considered investigational and/or experimental.

References

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familial hypercholesterolemia: the younger, the better. Circulation. i 2007;116(6):664-8. m 6. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus e conventional lipid lowering on atherosclerosis progression in familial l

hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. o Lancet. 2001 Feb 24;357(9256):577-81. r e 7. Neil HA, Hammond T, Huxley R, Matthews DR, Humphries SE. Extent of t underdiagnosis of familial hypercholesterolaemia in routine practice: prospective s e

registry study. BMJ. 2000;321(7254):148. l

8. Pucci G, Cicero AF, Borghi C, Schillaci G. Emerging biologic therapies for o

hypercholesterolaemia. Expert Opin Biol Ther. 2017 Jun 15:1-11. h c

9. Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin r

Genet. 2004;66(6):483-7. e

10. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic p heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J y

Epidemiol. 2004 Sep 1;160(5):407-20 H

l 11. Cardiac Society of Australia and New Zealand (CSANZ). Guidelines for the a

diagnosis and management of Familial Hypercholesterolaemia. Available at: i l

http://www.csanz.edu.au/wp- i content/uploads/2013/12/Familial_Hypercholesterolemia_2013.pdf. m a F

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12. van Aalst-Cohen ES, Jansen AC, Tanck MW, et al. Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Eur Heart J. 2006 Sep;27(18):2240-6. 13. Varret M, Abifadel M, Rabès JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008 Jan;73(1):1-13. 14. Hopkins, PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the national lipid association expert panel on familial hypercholesterolemia. (2011). Journal of Clinical Lipidology. 2011;5(3):S9-S17. 15. Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet. 2008;11(1):26-35. 16. National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia (FH) Full guideline. August, 2008 (Reaffirmed 2014; 2016 update). 17. Wiegman A, Gidding SS, Watts GF, et al. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015 Sep 21;36(36):2425-37. 18. U.S. Food and Drug Administration. FDA News Release: FDA approves Praluent to a

treat certain patients with high cholesterol. July 24, 2015. Available at: i https://wayback.archive- it.org/7993/20170722173020/https://www.fda.gov/NewsEvents/Newsroom/PressAn m e

nouncements/ucm455883.htm. l

19. U.S. Food and Drug Administration. FDA News Release: FDA approves Repatha to o r treat certain patients with high cholesterol. August 27, 2015. Available at: e

https://wayback.archive- t

it.org/7993/20170112023752/http://www.fda.gov/NewsEvents/Newsroom/PressAnn s

ouncements/ucm460082.htm. e l o h c r e p y H

l a i l i m a F

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