Delineating the trajectory of adult chronic diseases and healthcare use for 22q11.2 microdeletion in a general population context

Background Children with complex genetic diseases increasingly survive to adulthood, but adult health is poorly understood. Using a genetics-first approach we investigated the incidence and accrual of cardiovascular and other outcomes in people with molecularly confirmed 22q11.2 microdeletion (22q-cases) compared with general population controls (population-comparators). Methods Using a retrospective matched cohort study design, we linked 365 adult 22q-cases (median age 32 years; 51% female) to health administrative data for ∼15 million individuals with universal healthcare, identifying 3,650 well-matched population-comparators. We used Poisson regression to estimate incidence rate ratios (IRRs) and 95% CI for five cardiovascular/risk conditions and other outcomes, and recurrent event modelling to assess their relative rate (RR) of accrual over a median 28 years of retrospective and prospective health data. Results Accrual of cardiovascular conditions occurred at a significantly greater relative rate (RR) in 22q-cases than population-comparators (RR 3.8, 95% CI 2.9–4.8; median ages 32, 31), even when restricting to 22q-cases with neither major congenital heart disease (CHD) nor schizophrenia (RR 3.6, 95% CI 2.4–5.4). Incidence was significantly greater in 22q-cases for hypertension and diabetes by age 18–24 (IRR 2.98, 95% CI 1.45–6.14; IRR 3.21, 95% CI 1.42–7.24, respectively), and by age 35–44 for heart failure. Other outcomes also showed increasing trajectories over young adult years in the 22q-case group, e.g., kidney disease, chronic obstructive pulmonary disease, healthcare resource use, and hospitalizations, including for individuals with neither CHD nor schizophrenia. Conclusion A population-based approach provided new evidence for accumulating illnesses over young adulthood, supporting the need for novel models of anticipatory care for adults with 22q11.2 microdeletion. A similar genetics-first strategy, defining cohorts with shared genetic changes, may facilitate understanding of premature aging mechanisms relevant to the general population.