Familial Hypercholesterolemia: A Reportable ACMG Secondary Finding
Learning Objectives and CME/Disclosure Information
This activity is intended for healthcare providers delivering care to women and their families.
After completing this activity, the participant should be better able to:
1. List the 3 common pathogenic variants in FH 2. Recall the inheritance pattern of FH
Estimated time to complete activity: 0.25 hours
Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project
Disclosure of Conflicts of Interest
Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.
The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.
Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.
Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.
Method of Participation and Request for Credit
Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Dec 31 2017 through Jan 25 2023, participants must read the learning objectives and faculty disclosures and study the educational activity.
If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.
For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.
Joint Accreditation Statement
In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physician Continuing Medical Education
Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Continuing Nursing Education
The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.
Familial Hypercholesterolemia (FH) is a disorder characterized by very high levels of LDL cholesterol (LDL-C) and is the most common inherited cardiovascular disease, with a prevalence of 1:200 to 1:250
May account for up to 3% of heart attacks in those < 60 years of age
Prevalence varies among population with high carrier rates in Old Order Amish (1:10) and South Africans of Ashkenazi Jewish (1:67) and Afrikaner descent (1:72-1:100)
Pathogenic variants in 3 genes – LDLR, APOB and PCSK9 – account for 70 to 95% of FH
FH has an autosomal dominant pattern of inheritance with incomplete penetrance
FH usually refers to the more common ‘heterozygous’ form where only one gene copy has a deleterious mutation
There is a rare, more severe ‘homozygous’ form of FH where someone inherits two mutated copies of the LDLR gene, one from each parent
NOTE: Because medical interventions can prevent severe morbidity and mortality, Familial Hypercholesterolemia is on the ACMG list of secondary findings. In summary, the ACMG document on reporting such findings makes the following recommendations:
In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge
An individual can ‘opt out’ of receiving secondary findings
KEY CLINICAL POINTS:
Findings may appear in childhood or adulthood
There are formalized diagnostic criteria using clinical and laboratory findings
Finding a pathogenic mutation in one of the related genes is considered the ‘gold standard’
Appropriate surveillance and treatment can result in good outcomes
Left untreated, there is a 50% chance of a coronary artery event by age 50 in men and 30% risk by age 60 in women
Treatment is multidisciplinary and includes, but is not limited to, specialists in cardiology, lipid management and genetics
Assess patient and correct for CVD risk factors such as diet, BP, smoking, obesity
Specialized pharmacotherapy including statins and other lipid reducing medication
In severe cases, LDL apheresis and liver transplant, although rare, may be required
Excessive cholesterol results in the following findings on clinical and radiologic exam
Atherosclerotic plaques in coronary arteries and proximal aorta
Corneal arcus – grey/white ring around the periphery of the cornea, a result of lipid deposit when seen in individuals < 45 years of age (common finding in older people)
What gene/protein is affected and what does it do?
LDLR – Low Density Lipoprotein Receptor: (Most commonly associated with FH) LDLR is the receptor that binds low density lipoproteins (LDLs), the primary cholesterol carrying proteins in the bloodstream
Reduction or damage to LDL receptors can lead to elevated LDL-C levels
APOB – Apolipoprotein B: APOB is the main apolipoprotein on chylomicrons and LDLs and is important in the functioning of the low-density lipoprotein receptor
PCSK9 – Proprotein Convertase Subtilisin / Kexin type 9: The PCSK9 protein reduces the number of LDL Receptors
Pathogenic variants result in a ‘gain-of-function’ reducing the number of LDL receptors more than usual, leading to higher LDL-C levels
FH is an autosomal dominant disorder
It appears that almost all affected individuals will have a parent who is a carrier of a pathogenic variant, meaning the new mutation rate is low
Risks to family members and future offspring:
If a parent of an affected individual carries a mutation, the brothers and sisters of that affected individual have a 50% chance of carrying the mutation
Offspring of affected individuals have a 50% chance of inheriting the mutation and therefore having FH
Preimplantation genetics and prenatal testing is available
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Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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