Abstract
Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders.
Highlights
Schizophrenia (SCZ) is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide [1]
We excluded 54 Copy Number Variations (CNVs) reported in the Database of Genomic Variants (DGV); the remaining CNVs were filtered to remove those lacking potential candidate genes using PubMed literature mining
In family B, none of the detected CNVs were previously reported to be pathogenic, neither did they co-segregate with phenotype
Summary
Schizophrenia (SCZ) is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide [1]. An aggregate score that is the sum of the weighted effect of all the markers together, the so-called, Polygenic Risk Score (PRS) gives a strong predictive ability for risk assessment in small target samples [6]. This later evidence emerged for the involvement of the few rare variants with moderate to high penetrance (Common Disease Rare Variant (CDRV) that contribute interactively [7,8], and akin to the near mendelian or oligogenic inheritance of the disease
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