Abstract
 

Towards understanding variation in neuropsychiatric outcomes: Lessons learned from 22q11DS

The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for
schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is
relatively common and one of the most extensively studied. This lecture will first outline recent
findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS,
and go on to address considerations that are important in interpreting such data and propose
potential implications for both the clinical care for and the empirical study of individuals with
22q11DS. We will zoom in on variable penetrance and pleiotropy with respect to
neurodevelopmental phenotypes in 22q11DS; phenomena that are consistently observed in the
context of virtually all rare pathogenic variants and that pose substantial challenges from
both a clinical and a research perspective. The focus will be on recent findings from 22q11DS,
including those involving outcome prediction, and we will hypothesize how 22q11DS research
can help elucidate mechanisms underlying variable expression and pleiotropy of
neurodevelopmental phenotypes: insights that are potentially relevant for 22q11DS and
beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.