Assessment of Potential Clinical Role for Exome Sequencing in Schizophrenia

Abstract

BackgroundThere is increasing evidence that certain genetic variants increase the risk of schizophrenia and other neurodevelopmental disorders. Exome sequencing has been shown to have a high diagnostic yield for developmental disability and testing for copy number variants has been advocated for schizophrenia. The diagnostic yield for exome sequencing in schizophrenia is unknown. MethodA sample of 591 exome sequenced schizophrenia cases and their parents were screened for disruptive and damaging variants in autosomal genes listed in the Genomics England panels for intellectual disability and other neurological disorders. ResultsPreviously reported disruptive de novo variants were noted in SETD1A, POGZ, SCN2A and ZMYND11.Although loss of function of ZMYND11 is a recognised cause of intellectual disability it has not previously been noted as a risk factor for schizophrenia. A damaging de novo variant of uncertain significance was noted in NRXN1. A previously reported homozygous damaging variant in BLM is predicted to cause Bloom syndrome in one case and one case was homozygous for a damaging variant in MCPH1, a result of uncertain significance. There were over 400 disruptive and damaging variants in the target genes in cases but similar numbers were seen among untransmitted parental alleles and none appeared to be clinically significant. ConclusionsThe diagnostic yield from exome sequencing in schizophrenia is low. Disruptive and damaging variants seen in known neuropsychiatric genes should not be automatically assumed to have an aetiological role if observed in a patient with schizophrenia.

The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

“…The first part of the path to resolving this problem has been clarified by the results of studies to date. Aggregating the existing knowledge, we are able to identify diagnostic genomic variants (e.g., Pathogenic or Likely Pathogenic variants in the American College of Medical Genetics and Genomics [ACMG] guidelines [135]) in 1-6% of schizophrenia patients by comprehensively analyzing rare variants [136][137][138][139], and to extract a small proportion of the population with high genetic risk (e.g., OR > 5) utilizing the overall profiles of common variants (i.e., PRS [140,141]). On the other hand, to our knowledge, there are no genetic tests for schizophrenia approved by the government and covered by health insurance.…”

Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia

“…For example, using WES, Daniel et al found that de novo mutations in protein coding genes explain only a small fraction of SCZ risk [ 11 ]. Another study using WES reported disruptive de novo variants screened from 591 exome-sequenced SCZ cases and their parents [ 12 ]. Although family based studies can exclude some confounding factors such as population structure differences, these studies cannot explain the relationship between multiple factors and SCZ.…”

Third-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia

“…Recently, a large collaborative study has identified rare coding variants in 10 genes that confer substantial risk for schizophrenia ( Singh et al, 2022 ). However, despite these discoveries, the diagnostic yield from exome sequencing in schizophrenia is low ( Balakrishna and Curtis, 2020 ) and disease-related RV can only be detected in a small proportion of schizophrenic patients. In addition, mutations in non-coding regions can still have significant impacts on gene expression, variants in non-coding regulatory genome elements may be involved in schizophrenia and account for part of the missing heritability.…”