Novel variants in SPTAN1 without epilepsy: An expansion of the phenotype

Abstract

We describe two unrelated children with de novo variants in the non-erythrocytic alpha-II-spectrin (SPTAN1) gene who have hypoplastic brain structures, intellectual disability, and both fine and gross motor impairments. Using agnostic exome sequencing, we identified a nonsense variant creating a premature stop codon in exon 21 of SPTAN1, and in a second patient we identified an intronic substitution in SPTAN1 prior to exon 50 creating a new donor acceptor site. Neither of these variants has been described previously. Although some of these patients' features are consistent with the known SPTAN1 encephalopathy phenotype, these two children do not have epilepsy, in contrast to reports about nearly every other patient with heterozygous SPTAN1 variants and in all patients with a variant near the C-terminal coding region. Moreover, both children have abnormal thyroid function, which has not been previously reported in association with SPTAN1 variant. We present a detailed discussion of the clinical manifestations of these two unique SPTAN1 variants and provide evidence that both variants result in reduced mRNA expression despite different locations within the gene and clinical phenotypes. These findings expand the motor, cognitive, and behavioral spectrum of the SPTAN1-associated phenotype and invite speculation about underlying pathophysiologies.

Keywords: SPTAN1; ataxia; cerebellar cognitive affective syndrome; cerebellar hypoplasia; early infantile epileptic encephalopathy; premature termination codon; splice acceptor site.

FIGURE 1

Photographs of Patient 1 showing dysmorphic features including flat mid-face, a broad nasal tip, prominent nasal bridge, epicanthal folds, and mild ptosis bilaterally

FIGURE 2

(a–d) MRI images from Patient 1 demonstrating microcephaly, small optic nerves bilaterally and otherwise normal neuroanatomy. (e–f ) MRI images from Patient 2 showing small volume cerebellum with left hemisphere more affected than right hemisphere

FIGURE 3

(a) Immunocytochemistry staining of fibroblasts from Patients 1 and 2 and a control patient. There were no gross morphologic distinctions between patients and control in SPTAN1 amount or distribution. DAPI stains nuclei; actin stains actin filaments. (b) ddPCR using probes specific for the variant sequences of Patients 1 and 2 demonstrated reduced expression of healthy RNA sequences and detectible expression of both patients’ variant sequences. (c) Western blot assay showing detection of alpha-II spectrin protein in both patients’ and control fibroblasts. SPTAN1 can be seen at ~285 kDa and a fainter band corresponding to the major splice isoform of SPTAN1 is present at 150 kDa. An additional band was expected at ~140 kDa for the truncated SPTAN1 protein for Patient 1 but was not seen. (d) The intensity of the 285 kDa band for Patient 1 was decreased by over 25% relative to the 285 kDa band of a control patient in an average across three Western blots (p < .001)