Clinical applications of schizophrenia genetics: genetic diagnosis, risk, and counseling in the molecular era

Abstract

Schizophrenia is a complex neuropsychiatric disease with documented clinical and genetic heterogeneity, and evidence for neurodevelopmental origins. Driven by new genetic technologies and advances in molecular medicine, there has recently been concrete progress in understanding some of the specific genetic causes of this serious psychiatric illness. In particular, several large rare structural variants have been convincingly associated with schizophrenia, in targeted studies over two decades with respect to 22q11.2 microdeletions, and more recently in large-scale, genome-wide case-control studies. These advances promise to help many families afflicted with this disease. In this review, we critically appraise recent developments in the field of schizophrenia genetics through the lens of immediate clinical applicability. Much work remains in translating the recent surge of genetic research discoveries into the clinic. The epidemiology and basic genetic parameters (such as penetrance and expression) of most genomic disorders associated with schizophrenia are not yet well characterized. To date, 22q11.2 deletion syndrome is the only established genetic subtype of schizophrenia of proven clinical relevance. We use this well-established association as a model to chart the pathway for translating emerging genetic discoveries into clinical practice. We also propose new directions for research involving general genetic risk prediction and counseling in schizophrenia.

Disclosure of psychiatric manifestations of 22q11.2 deletion syndrome in medical genetics: A 12‐year retrospective chart review

“…Parents of children with 22qDS and individuals with the condition themselves cite consultation with specialists as one of the benefits of a genetic diagnosis [Costain et al, 2011]. It has also been suggested that the greatest potential benefit of early diagnosis of 22qDS is the ability to recognize the early stages of schizophrenia or other psychiatric illness, allowing prompt consultation or diagnosis from experts, followed by effective treatment [Bassett and Costain, 2012]. Clinical practice guidelines for the management of patients with 22qDS recommend repeated psychiatric assessments beginning as early as age 1, suggesting medical providers pay vigilant attention to changes in behavior or emotional state [Bassett et al, 2011;Habel et al, 2011].…”

The human clinical phenotypes of altered CHRNA7 copy number

“…For total parental inheritance, significantly (p<0.0001) more BP4-BP5 deletions were transmitted maternally (n=51, 73.9%) than paternally (n=18, 26.1%). Five cases had an additional genetic aberration that may be contributing to their phenotypes, including 16q duplications [37, 8], and mosaic Turner syndrome [39] (Table II). …”

Screening for rare epigenetic variations in autism and schizophrenia

“…Autism and schizophrenia are common neurological disorders that are estimated to affect 1% and 0.75% of the worldwide population, respectively (Bassett & Costain, ). Whereas both disorders are highly polygenic, microarray and exome sequencing studies have enabled the discovery of multiple highly penetrant genetic risk factors in these disorders, including rare inherited and de novo single nucleotide variants (SNVs; De Rubeis et al, ; Genovese et al, ; McCarthy et al, ; Mowry & Gratten, ; O'Dushlaine et al, ; O'roak et al, ; Sklar et al, ; Wormley et al, ) and copy number variations (CNVs; De Rubeis & Buxbaum, ; Szatkiewicz et al, ).…”