The purpose of this study is to evaluate the effectiveness of two models of cascade testing in identifying at-risk family members of individuals diagnosed with familial hypercholesterolemia (FH).

1. Index Patient Genetic Testing (only index patients from the REP database):

   • Index patients identified through the REP database will undergo confirmatory FH testing HCHLG panel
   • A sputum collection kit is mailed to participants along with a pre-addressed return mailer.
   • Results are recorded in the electronic medical record and communicated to index (REP) participants with next-step instructions.
   • Only index patients with confirmed pathogenic/likely pathogenic variants proceed in the study.

2. Relative Genetic Testing:

   • Relatives in the intervention arm who contact the study team and consent will be mailed a Focused Molecular Targeted Test (FMTT) sputum kit.
   • Testing targets the specific FH variant identified in the corresponding index patient.
   • Testing costs are covered **only** for relatives in the intervention arm.
   • Control arm relatives may choose to pursue clinical genetic testing independently through their primary care provider referring them to genetic counselling (usual care).

3. Baseline Data Collection (Index Patients):

   • Collection of demographics and FH-related history via REDCap.
   • LDL-C values abstracted from EMR; ROI used if external records are required.

4. Randomization:

   • Index patients randomized 2:1 to intervention or control arm.
   • Randomization occurs only after completion of baseline survey.

5. Intervention Arm Procedures:

   Indirect contact:

   In the CASCADE-FH trial, index patients receive IRB-approved recruitment letters, with contact information for the primary care study team, to distribute to up to three first- or second-degree relatives. Relatives who contact the team undergo screening and electronic consent. In this study, index patients choosing the indirect pathway are provided with structured Mayo approved educational materials to support the index patient in accurate and consistent communication with relatives.

   Direct Contact:

   In the CASCADE-FH trial, modified direct contact is operationalized through an IRB approved recruitment letter sent by the index patient to their relatives with contact information for the primary care study team. No direct outreach from the study team occurs unless a relative independently initiates contact to the study team.

   Relatives who contact the team undergo screening and electronic consent. After consent the primary care study team will be able to provide direct support to the at-risk relatives, provide Mayo-approved patient educational materials, and inform them of their potential risk for FH and the opportunity for genetic testing. This approach allows the primary care study team to provide a more direct method of communication and interaction with the at-risk relatives. The study team will also facilitate genetic testing, should the relative wish to proceed with genetic testing for FH.

   • Intervention-arm relatives receive FMTT sputum kits paid for by the study.

6. Control Arm Procedures:

   • Index patients receive usual care. No structured outreach is provided.
   • Relatives may seek genetic testing for FH through their primary care provider referring them to genetic counselling.
   • The study does not cover genetic counseling or testing costs in the control arm.

7. Relative Procedures (All Arms):

   • Relatives who contact the research team receive full study information and undergo screening and consent.
   • Baseline surveys collected via REDCap.
   • Minors require parental consent and age-appropriate assent.

8. Follow-Up Surveys:

   • Index patients and relatives receive surveys at 1, 3, and 12 months via REDCap.
   • Up to two reminder emails are sent approximately 7 days apart.
   • Participants who do not respond after reminders are classified as lost to follow-up.

9. Genetic Testing Workflow:

   • Returned sputum kits will be processed.

   • Results entered into EMR for all participants.

   • index (REP) participants and relatives in the intervention arm are notified via secure message or email on next steps.

     • Index (REP) participants who test positive are instructed to follow up with their primary care provider.
     • Follow-up for Positive Findings for Relatives in the intervention arm:

Participants who receive a pathogenic or likely pathogenic result for FH will be notified via secure patient portal or email. Notifications will instruct the participant to contact their primary care provider for referral to genetic counseling and/or preventive cardiology.

Parents or guardians of minors aged 1-18 years who test positive will be instructed to contact the child's primary care provider to obtain referral to a pediatric endocrinologist.

Inclusion Criteria:

Index Patients:

• Age ≥ 18 years.
• Confirmed FH diagnosis using Dutch Lipid Clinic Network criteria *or* genetic confirmation.
• Identified through REP or Tapestry databases.
• Able and willing to provide informed consent.
• At least one eligible first- or second-degree relative.
• Access to and active use of email (computer literacy requirement).

Relatives:

• First- or second-degree relative of an enrolled index patient.
• Age ≥ 1 year (minors require parental consent + assent).
• Willing to participate and able to complete electronic consent (guardian-assisted if minor).
• Access to and active use of email (guardian).

Exclusion Criteria:

Index Patients:

• No confirmed FH diagnosis.
• Insufficient clinical follow-up (<5 years).
• No identifiable or contactable relatives.
• Prior participation in structured cascade testing.
• Severe cognitive impairment preventing informed consent.

Relatives:

• Prior participation in structured cascade testing.
• Severe cognitive impairment preventing informed consent.