Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

Costin Leu,Lisa-Marie Niestroj,Robyn M Busch,Arthur Stefanski,Dennis Lal,Lara Jehi,Lisa Ferguson,Imad M Najm,Jocelyn F Bautista,Mark J Daly,Monica Sudarsanam

doi:10.1038/s41598-020-72101-8

Abstract

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ2), P = 0.30; PNES vs. epilepsy (2 × 2 χ2), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

Highlights

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers
550 individuals with epilepsy or PNES were included in the downstream analyses (Table 1)
The PNES group showed the highest proportion of individuals with comorbid psychiatric disorders or a history of chronic pain compared to the two epilepsy groups (Table 1)

Summary

Introduction

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. We considered genes associated with neurological or psychiatric disorders as candidate genes for PNES We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). The upper ranges of the estimates for a positive family history of psychiatric disorders and epilepsy are driven by the inclusion of individuals with PNES and comorbid epilepsy Such individuals were not routinely excluded in the majority of all PNES studies. Because the genetic basis of PNES is unknown and no established PNES genes exist, we applied the ACMG-AMP guidelines for research purposes only and considered genes associated with neurological or psychiatric disorders as candidate genes for PNES.

Methods

Results

Conclusion