Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation

Abstract

Objective: IRF2BPL mutation has been associated with a rare neurodevelopmental disorder with abnormal movements, including dystonia. However, the role of IRF2BPL in dystonia remains elusive. We aimed to investigate IRF2BPL mutations in a Taiwanese dystonia cohort.

Methods: A total of 300 unrelated patients with molecularly unassigned isolated (n = 256) or combined dystonia (n = 44) were enrolled between January 2015 and July 2023. The IRF2BPL variants were analyzed based on whole exome sequencing. The in silico prediction of the identified potential pathogenic variant was performed to predict its pathogenicity. We also compared the clinical and genetic features to previous literature reports.

Results: We identified one adolescent patient carrying a de novo heterozygous pathogenic variant of IRF2BPL, c.379C>T (p.Gln127Ter), who presented with generalized dystonia, developmental regression, and epilepsy (0.33% of our dystonia cohort). This variant resides within the polyglutamine (poly Q) domain before the first PEST sequence block of the IRF2BPL protein, remarkably truncating the protein structure. Combined with other patients with IRF2BPL mutations in the literature (n = 60), patients with variants in the poly Q domain have a higher rate of nonsense mutations (p < 0.001) and epilepsy (p = 0.008) than patients with variants in other domains. Furthermore, as our index patient, carriers with substitutions before the first PEST sequence block have significantly older age of onset (p < 0.01) and higher non-epilepsy symptoms, including generalized dystonia (p = 0.003), and ataxia (p = 0.003).

Interpretation: IRF2BPL mutation is a rare cause of dystonia in our population. Mutations in different domains of IRF2BPL exhibit different phenotypes.

Figure 1

Neuroimaging and electroencephalogram studies of the index patient with IRF2BPL c.379C>T (p.Gln127Ter) mutation. (A) T2‐weighted axial view and T1‐weighted sagittal view of brain MRI. (B) electroencephalogram. (C) ^99mTc‐TRODAT single‐photon emission computed tomography scan.

Figure 2

Family pedigree and genetic analysis of the index patient. (A) Pedigree of the index patient. Open symbol: unaffected; filled symbol: affected; arrow: proband. (B) Sanger sequencing traces confirm the de novo heterozygous c.379C > T (p.Gln127Ter) mutation in IRF2BPL. (C) Reported pathogenic variant, including the reported p.Gln127Ter variant (underlined) identified in the current study on the individual protein domain of IRF2BPL.

Figure 3

In silico protein structures of wild‐type and mutant IRF2BPL. (A) The mutated nucleotide of p.Gln127 is located within the N‐terminal coiled‐coilstructure of the poly Q domain of the IRF2BPL protein. (B) The truncated mutant IRF2BPL protein harboring the nonsense p.Gln127Ter mutation.