Background 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. In a minority of patients, the underlying 22q11.2 deletion is found to have been inherited, usually from an affected mother. Serious neuropsychiatric conditions that are commonly associated features of 22q11.2DS could disproportionately affect reproductive success in males.
Methods This study compared standard measures of reproductive fitness (mean number of liveborn offspring and proportion childless) in 141 Canadian adults with 22q11.2DS (cases) and their 200 unaffected siblings (controls). Multivariate regression models were used to identify phenotypic predictors of fitness in 22q11.2DS.
Results The adults with 22q11.2DS had significantly fewer children than their siblings (p<0.0001, relative fitness=0.28); 85.8% were childless. As expected, younger age (p<0.0001), mental retardation (p=0.0211), and schizophrenia (p=0.0046) were significant negative predictors of reproductive fitness in 22q11.2DS; however, serious congenital heart disease was not. Female sex emerged as a significant positive predictor of fitness independent of the major neuropsychiatric phenotypes (p=0.0082). Post-hoc analyses corroborated these sex differences. Notably, fitness in women with 22q11.2DS with neither mental retardation nor schizophrenia was not significantly different from that of unaffected female siblings.
Conclusions There is a strong negative selective pressure against 22q11.2 deletions. This appears to be primarily mediated by the severity of the neuropsychiatric phenotype and an independent sexual selection effect. The latter also contributes to the observed excess of transmitting mothers. These results may have implications both for the evolutionary biology of this structural rearrangement and for genetic counselling and reproductive services for adolescents and adults with 22q11.2DS.
- 22q11 deletion syndrome
- DNA copy number variations
- genetic fitness
- reproductive health services
- psychotic disorders (incl schizophrenia)
- genetic screening/counselling
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Funding This work was supported by Canadian Institutes of Health Research grants (MOP-97800 and MOP-89066), a Vanier Canada Graduate Scholarship (GC), and a Canada Research Chair in Schizophrenia Genetics and Genomic Disorders (ASB). The funding organisation played no role in the design of the study, the collection or interpretation of data, the preparation of the manuscript, or the decision to publish.
Competing interests None.
Ethics approval Centre for Addiction and Mental Health Research Ethics Board (Toronto, Ontario).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Pertinent raw data are in supplementary table 1.