RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes

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.

Fig. 1. Framework and additional cases.

a Study framework to verify candidate mutations resulting in severe Mendelian RCL1 phenotypes. b RCL1 copy number deletions (red) and duplications (blue) identified in academic medical centers in this study. Phenotypes consist of a range of neuropsychiatric features, individuals numbered 1–13. Note that individuals 8 and 9 were too young to display psychiatric symptoms. The genomic alignment panel includes genes surrounding RCL1 on chromosome 9 (9p24.1), which consists of 11 exons encompassing 68 kb, and additional RCL1 isoforms (color figure online).

Fig. 2. RCL1 expression in human brain development.

a Bulk transcriptome analysis of prefrontal cortical regions demonstrates RCL1 transcripts enriched during gestational weeks (WKSG) and decrease postnatally, presented as log₂ RPKM (reads per kilobase per million) values. DFC dorsolateral prefrontal cortex, VFC ventrolateral prefrontal cortex, MFC medial frontal cortex, OFC orbital frontal cortex. Transcriptome data from Allen Institute for Brain Science Atlas. b Confocal fluorescence image of a mid-gestation human coronal fetal cortex tissue with RCL1 antibody co-labeling with markers, glial fibrillary acidic protein (GFAP), a neuronal marker (NeuN), and nuclei marker (DAPI). RCL1 is lowly, yet uniformly present across developing cortex layers, with an abundant signal within the cortical plate. Scale bar 100 µm. MZ marginal zone, IMZ intermediate (fiber) zone, oSVZ outer sub-ventricular zone, VZ ventricular zone. RCL1 and cell type specific antibody staining with corresponding confocal fluorescence imaging of (c) 9-month-old human cortex (neonatal) and (d) adult cortex (37-year-old). Neuronal marker (NeuN) and global nuclei marker (DAPI) show RCL1 present in both neurons and non-neuronal cell types. Arrows indicate cells colocalized for NeuN and RCL1. Scale bar, 50 µm.