The cognitive profile of the schizophrenia-associated 3q29 deletion syndrome and the reciprocal 3q29 duplication syndrome

3q29 deletion syndrome (3q29del) and the reciprocal 3q29 duplication syndrome (3q29dup) are associated with a range of neuropsychiatric phenotypes, including impaired cognition. However, previous sample sizes have been small, and cognitive performance has not been systematically compared between 3q29del and 3q29dup. For both disorders, the impact of familial background on cognition is unknown. 3q29del is associated with high risk for schizophrenia; in the general population individuals at Clinical High Risk (CHR) for psychosis exhibit impaired cognition, but the relationship between CHR status and cognition in 3q29del is unexplored. Here we address these questions in the largest sample of 3q29del and 3q29dup ever evaluated. Individuals with 3q29del (n=103, 58.3% male), 3q29dup (n=38, 55.3% male), and controls (n=54, 42.6% male) were assessed with the Peabody Picture Vocabulary Test, 5th Edition (PPVT-5) and the Penn Computerized Neurocognitive Battery (Penn-CNB). Total PPVT-5 scores and global, domain-level, and task-level Penn-CNB scores were compared across groups. Compared to controls, 3q29del participants scored an average of 24.6 and 22.9 points lower on the PPVT and Penn CNB, respectively (p<3E-16); 3q29dup participants scored an average of 18.8 and 14.2 points lower on the PPVT and Penn CNB (p<4E-6). In addition, 3q29del and 3q29dup exhibit unique profiles of cognitive deficits. To assess the impact of familial background on cognition, we evaluated unaffected relatives of 3q29del (n=140, 38.6% male), 3q29dup (n=25, 24.0% male), and controls (n=45, 11.1% male). The average familial shift on the Penn-CNB was 22.4 points for 3q29del and 16.7 points for 3q29 dup. Individuals with 3q29del+CHR exhibited greater cognitive deficits than 3q29del-CHR. These results demonstrate that both 3q29del and 3q29dup are associated with significant cognitive impairment and indicate that cognitive testing should be standard of care for individuals diagnosed with 3q29del or 3q29dup.