De novo variants in sporadic cases of childhood onset schizophrenia

Abstract

Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.

Figure 1

Dot plot shows the distribution of de novo variants in 17 COS probands. The x axis represents the de novo mutation rate per individual. The line in red indicates the fairly accurate coding de novo mutation rate reported so far.

Figure 2

Violin plot showing the distribution of functional severity, predicted by bioinformatics scores, for the missense de novo variants and private inherited variants in COS probands. Also shown is the comparison of de novo variants in schizophrenia reported by our group and other controls in recent studies.^, The median is indicated by the white dot and the colored area shows the kernel distribution of the data. (a) PolyPhen-2 score—variant based and the higher score shows more severity. (b) RVIS, Residual Variant Intolerant Score is gene specific and lower score shows more intolerant for variation.