Assessment of Potential Clinical Role for Exome Sequencing in Schizophrenia

Thivia Balakrishna; David Curtis


Schizophr Bull. 2020;46(2):328-335. 

In This Article

Abstract and Introduction


Background: There 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.

Method: A 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.

Results: Previously reported disruptive de novo variants were noted in SETD1A, POGZ, SCN2A, and ZMYND11. Although the loss of function of ZMYND11 is a recognized 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 1 case and 1 case was homozygous for a damaging variant in MCPH1, a result of uncertain significance. There were more than 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.

Conclusions: The 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 etiological role if observed in a patient with schizophrenia.


It is now well established that deletions and duplications at specific chromosomal locations, termed copy number variants (CNVs), can have a substantial effect on the risk of developing schizophrenia and are found in 3% of people with schizophrenia who have normal IQ and 7% of those with borderline IQ.[1,2] Because of their clinical implications, it has been advocated that testing for these pathogenic CNVs should be a routine investigation for patients diagnosed with schizophrenia.[3] Identifying a CNV with a substantial effect on risk could help by providing the patient with an explanation of why they have become unwell and might improve compliance with treatment, as well as having implications for relatives.[4] As well as CNVs, polygenic risk factors and non-genetic risk factors, there is now good evidence that rare coding variants contribute to schizophrenia risk.[5] There is strong statistical evidence that schizophrenia cases have an excess burden of rare variants predicted to damage the function of particular sets of genes, eg, those related to synaptic functioning.[6,7] However, only a small number of individual genes are strongly implicated. Currently, we would argue that there is good evidence to support the claim that variants causing loss of function (LOF) of SETD1A, RBM12, and NRXN1 can substantially increase the risk of schizophrenia.[8–10] However, these are extremely rare and are collectively found in fewer than 1% of cases.

It has become apparent that the relationship between genotype and phenotype is often more complex than had originally been supposed and that variants which had been thought to have a simple Mendelian effect might manifest reduced penetrance.[11] In the context of psychiatric disorders, an important general theme which emerges from the findings to date is that a variant which confers increased risk of schizophrenia may also confer increased risk of intellectual disability (ID) or other neurodevelopmental disorder, suggesting a form of pleiotropy in that processes which disrupt neurodevelopment may lead to ID, schizophrenia, both, or neither. This applies to both CNVs and, eg, LOF variants of SETD1A, which are found both in schizophrenia cases and in subjects diagnosed with the developmental disorder.[8] In general, we find that rare, damaging coding variants in schizophrenia cases affect genes implicated in other neurodevelopmental disorders.[12] Another example is a recently reported case with a de novo variant in SCN2A who initially presented with infantile-onset seizures, autistic features, and episodic ataxia but then developed psychotic symptoms as an adult.[13]

In contrast to schizophrenia, several hundred genes are implicated as risk factors for ID, in the sense that it is known that specific variants in these genes can produce a phenotype, which includes ID. Given the pleiotropy described earlier, if one detected in a patient with schizophrenia a variant known to cause ID then one might reasonably conclude that in this case, the variant was likely making an etiological contribution to the schizophrenia. Testing for variants in known ID genes, rather than only the handful of currently known schizophrenia genes, might produce a worthwhile diagnostic yield and this approach has been implemented in a pilot study incorporated in the 100 000 Genomes Project, a diagnostic service implemented by the UK National Health Service. Here, patients with schizophrenia accompanied by other features suggestive of a genetic etiology undergo whole-genome sequencing and are then checked for variants in genes known to be causative of ID and other neurological conditions. In children with severe developmental disorders, exome sequencing can produce an overall diagnostic yield of about 40%.[14] We thought it would be of interest to gain a better understanding of what the likely yield might be for patients with schizophrenia by applying the proposed diagnostic testing protocol to a sample of research subjects for whom exome sequencing data were already available.

The Bulgarian sample consists mainly of a set of schizophrenia cases along with their parents who have undergone exome sequencing and who have been studied for the presence of de novo mutations and recessively acting variants.[15,16] These previous reports were gene discovery projects aiming to build evidence to identify novel genes conferring susceptibility to schizophrenia, and indeed provided some of the evidence to implicate SETD1A. We set out to use this sample as if it were a clinical sample with the aim of identifying any variants, acting dominantly or recessively, which might in a clinical context be reported as pathogenic or likely pathogenic.