Abstract
The clinical similarity among different neuropsychiatric disorders (NPDs) suggested a shared genetic basis. We catalogued 23,109 coding de novo mutations (DNMs) from 6511 patients with autism spectrum disorder (ASD), 4,293 undiagnosed developmental disorder (UDD), 933 epileptic encephalopathy (EE), 1022 intellectual disability (ID), 1094 schizophrenia (SCZ), and 3391 controls. We evaluated that putative functional DNMs contribute to 38.11%, 34.40%, 33.31%, 10.98% and 6.91% of patients with ID, EE, UDD, ASD and SCZ, respectively. Consistent with phenotype similarity and heterogeneity in different NPDs, they show different degree of genetic association. Cross-disorder analysis of DNMs prioritized 321 candidate genes (FDR < 0.05) and showed that genes shared in more disorders were more likely to exhibited specific expression pattern, functional pathway, genetic convergence, and genetic intolerance.
Highlights
Neuropsychiatric disorders (NPDs) are a group of disorders with brain dysfunction, leading to abnormal in cognition, behavior, mood and communication
After controlling for batch effects with synonymous variants, we found that all the five neuropsychiatric disorders (NPDs) carried significantly more LoF and deleterious missense variant (Dmis) de novo mutations (DNMs), as well as the combination of these two classes of DNMs (i.e., putative functional (Pfun)) but not tolerant missense variant (Tmis) DNMs, suggesting that Pfun DNMs are involved in all the five disorders (Table 1; Fig. S1)
Our data showed that Pfun DNMs rather than Tmis and synonymous DNMs play broad roles in the five NPDs, along with compellingly different degrees of DNM burden and contribution to phenotypes
Summary
Neuropsychiatric disorders (NPDs) are a group of disorders with brain dysfunction, leading to abnormal in cognition, behavior, mood and communication. The similarity and heterogeneity among different types of NPDs such as autism spectrum disorder (ASD), epileptic encephalopathy (EE), intellectual disability (ID), and schizophrenia (SCZ), undiagnosed developmental disorder (UDD) promote clinicians and researchers studying them. These disorders tend to strike before adolescence, in particular ASD, EE, ID, and UDD onset during the time of infant and child. Due to the dynamic nature of symptoms, patients often receive diagnoses of additional disorders, particular within the first year of the original diagnosis, and these pair comorbidities were bidirectional (Plana-Ripoll et al, 2019) All of these studies highlight the clinical similarity among NPDs, which implicated common etiological mechanisms
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