Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d9528692e468">Background</h5> <p id="P3">While the pathogenic nature of CNVs on chromosome 22q11.2 have been recognized for decades, unbiased estimates of their population prevalence, mortality, disease risks, and diagnostic trajectories are lacking. Hence, we aim to provide the true population prevalence, trajectory of disease risk, and mortality of 22q11.2 CNVs utilizing the unbiased, representative Danish iPSYCH population case-cohort. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d9528692e473">Methods</h5> <p id="P4">We use epidemiological methods in conjunction with nationwide hospital registers to analyze the iPSYCH case-control cohort i.e. cases born from 1981 to 2005 (n=57,377) with Attention-Deficit/Hyperactivity Disorder, Major Depressive Disorder, Schizophrenia, Autism or Bipolar Disorder as well as 30,000 randomly drawn individuals – to provide unbiased, population-adjusted estimates and 30-year long disease trajectories for major neuropsychiatric disorders. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d9528692e478">Findings</h5> <p id="P5">Population prevalence in the Danish population was 1:3672 and 1:1606 for deletions and duplications, respectively, the mortality rate was zero and hazard ratios for neuropsychiatric disorders ranged from 1 to 82 comparably for both rearrangements. By age 32, 10% developed Attention-Deficit/Hyperactivity Disorder, Autism or Intellectual Disability; and deletion carriers had higher probability than duplication carriers of co-occurring Intellectual Disability and of epilepsy. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d9528692e483">Interpretation</h5> <p id="P6">The significantly different prevalence of 22q11.2 duplications and deletions indicates distinct selective pressures on these rearrangements. While risk for congenital abnormalities, developmental delay, and Intellectual Disability is elevated in deletion carriers, the overall prevalence of neuropsychiatric disorders is higher in duplication carriers, which implies that identification and clinical monitoring should extend beyond congenital traits and into child and adolescent psychiatry. </p> </div>