Complex disease
The patient is in front of you and does not fit. The chart is long, the referrals are many, and no single diagnosis explains the whole picture. This domain asks where the genomic signal is in that patient and how an independent physician, with time and a few peers, can find it.
Why this is a domain
Complex, multisystem illness is where primary care spends its hardest hours and where the genetic contribution is most often missed. The usual system has fifteen minutes and a referral pathway; it fragments the patient across specialties, each of which sees a normal organ. Independent practice has the visit length to hold the whole patient but rarely a peer to think with. The five cohorts here are five recurring shapes that the undiagnosed patient takes, each with its own anchor question and its own care map.
The through-line is that the outlier is the signal. A registry of patients referred for hypermobile EDS evaluation found an alternative or additional genetic diagnosis, with distinct management, in 26.4% of those who met the clinical criteria.1 In families with prior inconclusive testing, genome sequencing still made a diagnosis in 15.3%, and more than half of those were in regions earlier tests had never examined.2 The patients who do not fit are not noise.
The five cohorts
| Cohort | Who it covers | Status | Slack |
|---|---|---|---|
| Connective tissue Is this hEDS or HSD, or a genetic connective tissue disorder that changes management? | hEDS, HSD, Marfan, Loeys-Dietz and heritable aortic disease, and the patients being sorted among them | Launch | #cohort-connective-tissue |
| Nonspecific symptoms What is the unifying diagnosis, if there is one, behind fatigue, pain, dysautonomia and cognitive symptoms? | Fatigue, pain, dysautonomia or cognitive symptoms with no unifying diagnosis after a standard workup | Forming | #cohort-nonspecific-symptoms |
| Specific signs This one objective finding points somewhere. Where? | An objective finding that points somewhere: an odd lab, an imaging finding, a dysmorphic feature, a family pattern with uninformative testing | Seeking a lead | #cohort-specific-signs |
| Progressive monogenic disease The diagnosis is known and the disease progresses. What does good care look like around the specialist's plan? | Diagnosed, progressive, multiorgan monogenic disease where the plan is coordination, surveillance and quality of life | Seeking a lead | #cohort-progressive-monogenic |
| Management and surveillance The diagnosis is established. Who is watching which organ, and when? | NF1, Marfan after diagnosis, Turner, 22q11.2 and similar in adults: lifelong multi-organ surveillance | Seeking a lead | #cohort-management-surveillance |
How the care maps differ here
In this domain, Year 1 is the hard year. The Establish cycle is mostly diagnostic: a structured phenotype, the right test rather than the first test, and a genetics role that is as much about deciding what not to order as what to order. Genome sequencing with reanalysis at 24 to 36 months appears on every map in the domain because the evidence favors it over sequential single-gene and panel testing when the phenotype is broad.2
Treat and Sustain look different from cohort to cohort. For connective tissue disease they are surveillance and symptom management. For progressive monogenic disease they are anticipatory care and the family. For management and surveillance they are a calendar, organ by organ, that the anchor physician owns so that no specialist assumes another one is watching.
Two roles are heavier in this domain than elsewhere: behavioral health, because long diagnostic odysseys harm people, and community, because patient organizations often hold the natural-history knowledge that the literature does not yet.
What the domain needs from the provider rosters
Advanced imaging with protocol requests honored; procedural studies, especially autonomic testing, echocardiography with aortic root reporting, and nerve conduction; esoteric assays including biochemical genetics; and specialists in cardiology, neurology, gastroenterology and rheumatology who will see a patient with a complicated chart and write back. The diagnostic support and private practice domains exist in large part to serve this one.
Starting references
- Forghani I, See J, McGonigle WC. Hypermobile Ehlers-Danlos syndrome: diagnostic challenges and the role of genetic testing. Genes (Basel). 2025;16(5). doi:10.3390/genes16050530
- Pitsava G, Hawley M, Auriga L, et al. Genome sequencing reveals the impact of pseudoexons in rare genetic disease. Genet Med. 2025;27(11):101574. doi:10.1016/j.gim.2025.101574
- Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26. doi:10.1002/ajmg.c.31552