A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity

Abstract

Epilepsy and Mental Retardation Limited to Females (EFMR) is an infantile onset disorder characterized by clusters of seizures. EFMR is due to mutations in the X-chromosome gene PCDH19, and is underpinned by cellular mosaicism due to X-chromosome inactivation in females or somatic mutation in males. This review characterizes the neuropsychiatric profile of this disorder and examines the association of clinical and molecular factors with neuropsychiatric outcomes. Data were extracted from 38 peer-reviewed original articles including 271 individual cases. We found that seizure onset ≤12 months was significantly associated (p = 4.127 × 10^-7) with more severe intellectual disability, compared with onset >12 months. We identified two recurrent variants p.Asn340Ser and p.Tyr366Leufs*10 occurring in 25 (20 unrelated) and 30 (11 unrelated) cases, respectively. PCDH19 mutations were associated with psychiatric comorbidities in approximately 60% of females, 80% of affected mosaic males, and reported in nine hemizygous males. Hyperactive, autistic, and obsessive-compulsive features were most frequently reported. There were no genotype-phenotype associations in the individuals with recurrent variants or the group overall. Age at seizure onset can be used to provide more informative prognostic counseling.

Fig. 1

Lollipop plot illustrating all the reviewed PCDH19-GCE variants (n = 271). Lollipop size is exponentially proportional to the number of times the variant has been observed. Recurrent (i.e., seen more than once in unrelated individuals) variants are located above the protein and labeled if they occur more than twice

Fig. 2

Genotype–phenotype association. a Circos plot illustrating the variable cognitive profile of PCDH19-GCE (n = 155) against age at seizure onset: ≤12 months (n = 124) and >12 months (n = 48). Recurrent variants p.Asn340Ser (n = 17) and p.Tyr366Leufs*10 (n = 23) are highlighted in red and blue, respectively. Axes show the number of individuals in each category. Illustration represents cases where relevant information was available. b Bar graph (±1 SEM) illustrating the association of age at seizure onset and ID severity (values from unadjusted linear model), ***p = 3.090 × 10⁻⁷. Cognitive function was scored on a scale: (0) “normal”, (1) “borderline”, (2), “mild ID”, (3) “moderate ID”, and (4) “severe/profound ID”, with higher scores indicating increased ID severity. Mean ID severity was derived by totaling the scores and dividing by the number of individuals in that group