Ultra-rare CHD2 stop-gain variant segregates with schizophrenia and autism across three generations in Azorean pedigree

Researchers sequenced 173 multiplex families from the isolated Azorean and Madeiran populations, where founder effects amplify rare alleles. In family PIC-9420, the CHD2 variant co-segregated perfectly with illness; it was absent from gnomAD, the PGC schizophrenia and bipolar cohorts, and appeared only once among 800,000 reference genomes. This observation extends prior CHD2 associations limited to epilepsy and autism, showing the same loss-of-function allele can produce adult-onset psychosis when transmitted in this genetic background. The finding aligns with emerging data from the iPSYCH and SCHEMA consortia that chromatin-remodeling genes harbor both ultra-rare and common risk variants for multiple neurodevelopmental diagnoses. Penetrance here is high yet phenotype expression varies, consistent with modifier effects from shared ancestry rather than diagnostic misclassification. Larger case-control studies dilute such signals because they lack the extended pedigrees needed to observe within-family heterogeneity. Next steps require functional assays in patient-derived neurons to test whether the variant alters chromatin accessibility at loci previously implicated in both schizophrenia and autism. Population-based resequencing of CHD2 in additional founder cohorts could establish whether this mechanism is private or recurrent at low frequency.