IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

Abstract

Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.

Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.

Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.

Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

Keywords: IQSEC2; X-linked inheritance; epilepsy; intellectual disability; isoforms.

Fig. 1

Schematic representation of IQSEC2 isoforms and location of pathogenic IQSEC2 variants on the longest isoform. (a) Schematic representation of the three IQSEC2 isoforms resulting from alternative promoter usage (P1 vs. P2) and splicing. Blue/gray boxes respectively indicate exons present/absent in the longest isoform. The pink star indicates the location of the IQSEC2 variant (unknown significance) identified in patient 47. (b) Location of IQSEC2 pathogenic variants reported in this study (above) or in the literature (below) on the schematic representation of the longest NM_001111125.2 isoform (numbered blue boxes correspond to exons) and corresponding protein domains: N-terminal coiled coil (CC) domain, IQ calmodulin-binding motif (IQ), SEC7 and Pleckstrin homology (PH) domains, and PDZ-binding motif (STVV). Square: predicted truncating variants; circle: missense variants; triangle: in-frame deletion; bow tie: splice variants; pink: variants present in affected females; blue: variants present in affected males; yellow: variants present in affected males and females. Red dot: de novo occurrence; green dot: maternal inheritance; orange dot: suspected gonadal mosaicism. No dot indicates inheritance is unknown. Horizontal lines indicate the extent of large deletions on the corresponding coding sequence. Variants underlined: previously published without clinical data and included in this study. Variants of unknown significance (VUS) or variants from the literature for which sex was unknown are not indicated on this schematic

Fig. 2

The PDZ-binding domain IQSEC2 isoform (NM_001111125.2 / NP_001104595.1) is the dominant form expressed specifically in brain. Expression of IQSEC2 isoforms across multiple tissues was quantified using two different methods. (a) Cap Analysis of Gene Expression (CAGE) data shows that the upstream transcription start site (P2), which gives rise only to NM_001111125.2/ENST00000396435.8, is strongly and specifically expressed in the brain while the downstream transcription start site (P1) is more broadly expressed across other tissues. Tissues were chosen based on relatively strong expression of any TSS and sample data, then grouped by tissue. (b) Isoform specific intron-spanning RNA-seq reads were quantified to show relative levels of isoform expression, again confirming that NM_001111125.2 is the dominant brain form. Between the two non-PDZ-binding domain forms (NM_001243197.1/ENST00000639161.1 and NM_015075.1/ENST00000375365.2) the shortest form NM_001243197.1 is the isoform predominantly expressed in nonneuronal tissues, and it is also weakly expressed in the brain. Tissues were chosen based on Fig. 2a, but are more limited due to data availability. All data are mean +/− SEM, individual sample data are provided in Table S3

Fig. 3

Comparison of ID severity, seizure onset, and pharmacoresistance in males and females with IQSEC2 variants. (a) Violin plots showing the distribution of intellectual disability (ID) degree in males (blue) and females (pink). The distribution of males is clearly shifted to the most severe end of the spectrum while cognitive impairment is on average less severe, but also more variable, in females. (b) Violin plots comparing the age at seizure onset in months (y-axis) in males (blue) and females (pink), illustrating that epilepsy tends to appear later in females. (c) Violin plots comparing the resistance to antiepileptic treatments (AETs) (y-axis) in males (blue) and females (pink), showing that epilepsy in males are on average more pharmacoresistant. (d) Absence of clear correlation between the degree of comparing the (y-axis) and age at seizure onset (x-axis). Blue circles: males; pink circles: females; mod: moderate; sev: severe; pro: profound. The numbers above indicate the patient ID number