Comprehensive genetic risk
The anchor question: this healthy adult had a proactive exome or genome, or wants one. What's actionable, what isn't, and what do the next ten years of their care look like because of it? The session three work on familial hypercholesterolemia lands here.
Status: Forming. Page and channel are up; the cohort needs a lead. The map below is a first draft, revised after the March 2027 session on FH and cascade testing.
Who this cohort covers
Adults without a diagnosis who have had, or are considering, genome-scale testing for risk: a proactive clinical exome or genome, a secondary-findings report from diagnostic testing, or a consumer test they want interpreted. The findings that matter most have established interventions: the three CDC Tier 1 conditions (hereditary breast and ovarian cancer, Lynch syndrome, familial hypercholesterolemia) and the wider ACMG secondary-findings list of cardiomyopathies, arrhythmias, aortopathies, cancer syndromes and metabolic conditions.1 Hereditary cancer syndromes found this way go to the hereditary cancer map. This cohort owns the decision to test, the cardiovascular and metabolic findings, and the whole-person plan.
Two population studies make the case. In the Healthy Nevada Project, 1.33% of 26,906 participants carried a pathogenic variant for a Tier 1 condition; 90% of them hadn't been identified before, and only a quarter reported a relevant family history.2 At Geisinger, 87% of participants with a Tier 1 result had no prior genetic diagnosis, 70% of those eligible had a recommended risk-management procedure after disclosure, and 13% received a relevant clinical diagnosis.3 Family history alone misses most carriers. For FH in particular, the barriers to diagnosis and cascade testing in primary care are documented and fixable.4
Care map
| Role | Year 1, Establish | Year 2, Treat | Year 3, Sustain |
|---|---|---|---|
| Anchor | The decision to test: what the patient wants to know, what they would do with it, who else it affects. Three-generation pedigree. Baseline lipids, blood pressure, ECG, cancer screening status. Pre-test counseling, in person or through the counselor roster. Test ordered with secondary findings explicitly opted in or out. | Translate each finding into a surveillance calendar and own it. Start or adjust therapy for FH and other metabolic findings. Refer per finding. | Annual review of the calendar and the pedigree. Reassess the report against updated gene lists.1 |
| Genetics | Choice of test and laboratory, with the ACMG secondary-findings list as the minimum actionable set.1 Post-test interpretation of every pathogenic or likely pathogenic finding and an explicit decision not to act on variants of uncertain significance. | Cascade testing for every actionable finding, with a family letter. Polygenic scores, if reported, placed in context with the monogenic result and the family history. | Reanalysis and reclassification check at 24 to 36 months. New actionable genes screened against the stored data. |
| Specialists | None by default. Cardiology for a cardiomyopathy, arrhythmia or aortopathy gene; lipid specialist for FH not at goal; the hereditary cancer map for cancer genes. | Per finding, with a written question and a return date. | Per finding. |
| Diagnostics | Baseline per finding: echocardiogram and ECG for cardiac genes, aortic imaging for aortopathy genes, lipoprotein(a) once, iron studies for HFE. | Surveillance interval per finding and guideline. | Same calendar, adjusted for age and findings. |
| Therapies | Exercise prescription adjusted for any cardiac finding. | Maintenance. | |
| Behavioral health and nutrition | Pre-test counseling on the psychological side of risk information; screen for health anxiety. | Dietitian for FH and metabolic findings. Support for family disclosure. | As needed. |
| Community | Condition-specific organizations once a finding exists; registry participation if the patient wants it. |
Visit one
| Ask | Why the patient wants testing and what they would do with each kind of result. Three-generation pedigree with cancers, early heart disease, sudden death, high cholesterol, aortic disease. Prior testing anywhere in the family, with the report. |
| Examine | Blood pressure, BMI, tendon xanthomas and corneal arcus, cardiac examination. |
| Order | Baseline lipids with lipoprotein(a), ECG. The test itself only after counseling, with the secondary-findings decision recorded.1 |
| Refer | Genetic counseling before testing where the patient wants it or the pedigree is complex. Where: the counselor roster as it forms, and the specialist roster once a finding exists. |
| Tell the patient | What the test can and can't find; that most reports contain nothing actionable, and that's a real result; that an actionable result means a calendar, not a diagnosis; what it means for relatives. |
| Document | The reason for testing, the pedigree, the counseling given, the secondary-findings choice, and the date the result will be reviewed. |
Roster for this cohort
Drawn from the counselor roster (genetic counselors who take cash-pay pre- and post-test visits), the esoteric assays roster (laboratories offering clinical exome or genome with transparent pricing and reanalysis), and the specialist roster (cardiology, lipidology). Forming; members propose and vet entries in the cohort's Slack channel.
Readings
- Grzymski JJ, Elhanan G, Morales Rosado JA, et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med. 2020;26(8):1235-1239. doi:10.1038/s41591-020-0982-5
- Miller DT, Lee K, Abul-Husn NS, et al. ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing. Genet Med. 2023;25(8):100866. doi:10.1016/j.gim.2023.100866
References
- Miller DT, Lee K, Abul-Husn NS, et al. ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023;25(8):100866. doi:10.1016/j.gim.2023.100866
- Grzymski JJ, Elhanan G, Morales Rosado JA, et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med. 2020;26(8):1235-1239. doi:10.1038/s41591-020-0982-5
- Buchanan AH, Lester Kirchner H, Schwartz MLB, et al. Clinical outcomes of a genomic screening program for actionable genetic conditions. Genet Med. 2020;22(11):1874-1882. doi:10.1038/s41436-020-0876-4
- Jones LK, Calvo EM, Campbell-Salome G, et al. Designing implementation strategies to improve identification, cascade testing, and management of families with familial hypercholesterolemia: an intervention mapping approach. Front Health Serv. 2023;3:1104311. doi:10.3389/frhs.2023.1104311