Abstract
Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3′-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.
Highlights
Large-scale studies of common variants provide insight into the genetic architecture of psychiatric disorders such as schizophrenia and bipolar disorder [1, 2]
After two additional near syncopal episodes, he was evaluated by a neurologist who concluded that the episodes were not likely seizures
We began with an index case of very early onset psychosis (VEOP) and utilized our systematic approach to identifying candidate genes for further investigation
Summary
Large-scale studies of common variants provide insight into the genetic architecture of psychiatric disorders such as schizophrenia and bipolar disorder [1, 2]. Even though these studies have involved hundreds of thousands of participants, they have typically explained only a small fraction of the genetic contribution to these focal illnesses, and have identified scores of loci that, with follow up, have pointed to putative risk genes [3,4,5]. These authors contributed : Catherine A Brownstein, Richard S.
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