Clinical spectrum of STX1B-related epileptic disorders

Abstract

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants.

Methods: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools.

Results: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes.

Conclusion: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Figure 1. STX1B gene with variants and pedigrees of newly identified variants

(A) Putative domain structure of syntaxin-1B derived from that for syntaxin-1A, as the isoforms share 83.6% of their amino acid sequences (using the alignment program ClustalO). Shown are the functional domains and depiction of variants. Missense variants are colored in black, other variants are shown in gray. The boxed variants represent developmental and epileptic encephalopathies. (B) Pedigrees of sporadic patients/families with newly identified variants. F21 was adopted and there was no information about the biological parents. Abs = absence seizure; AS = atonic seizure; atyp. = atypical; CPS = complex partial seizure; FE = focal epilepsy; FIAS = focal impaired awareness seizure; GEFS+ = genetic epilepsies with febrile seizures plus; GGE = genetic generalized epilepsy; GTCS = generalized tonic-clonic seizure; IS = infantile spasms; Myo = generalized myoclonic seizure; TMR = transmembrane region; TS = tonic seizure.

Figure 2. Mutational density and paralog conservation scores of STX1B missense variants

(A) Putative domain structure of syntaxin-1B (figure 1A). (B) Variation density in STX1B amino acid positions according to the Genome Aggregation Database (gnomAD) depicting the reported missense variants. (C) Paralog conservation score (para_zscore) of the STX1B amino acid positions depicting the reported missense variants (positive values are considered as paralog conserved). Previously reported variants are colored in gray, new variants in black. TMR = transmembrane region.

Figure 3. Mutational density and paralog conservation score of different gene regions

(A) Distribution of mutational density of 4 STX1B gene regions. The SNARE motif shows the lowest mutational density, the transmembrane region (TMR) the highest density. (B) Paralog conservation score (para_zscore) distribution of 4 STX1B gene regions. The SNARE motif shows the highest paralog conservations, the TMR the lowest conservation. (C) Comparison of paralog conservation score for all Genome Aggregation Database (gnomAD) variants and patient variants.