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-IIspectrin (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. K E Y W O R D Sataxia, cerebellar cognitive affective syndrome, cerebellar hypoplasia, early infantile epileptic encephalopathy, premature termination codon, splice acceptor site, SPTAN1

The Role of Nonerythroid SpectrinαII in Cancer

“…As the last two spectrin repeats are required for heterodimer formation, mutations in this C-terminal region of SPTAN1 are critical and might have major consequences. In addition, Gartner et al [107] suggested that deleterious variants of SPTAN1 may cause reduced mRNA expression as observed in two unique SPTAN1 variants.…”

De novo SPTAN1mutation in axonal sensorimotor neuropathy and developmental disorder

“…Our patient's neuropathy and neuropsychological profile provide an interesting link between axonal neuropathy phenotypes described by Beijer et al, and previously described non-epileptic neurodevelopmental phenotypes. Gartner et al reported two patients, aged 12 and 7, with de novo nonsense or splice mutations that decreased the level of alpha-II spectrin (Gartner et al, 2018) consistent with a haploinsufficiency mechanism. These patients resembled our patient by having developmental disorder and impairment of motor performance from early age.…”

“…Before this, alterations of SPTAN1 have been linked to early-infantile epileptic encephalopathy or neurodevelopmental phenotypes often with epilepsy (Syrbe et al, 2017;Gartner et al, 2018) . De novo in-frame deletions/duplications, missense, truncating and splice mutations have been described behind these phenotypes.…”

“…De novo in-frame deletions/duplications, missense, truncating and splice mutations have been described behind these phenotypes. The in-frame insertions/deletions are likely to cause dominant negative effects (Saitsu et al, 2010;Huang et al, 2017), whereas splice and truncating mutations decrease mRNA levels of SPTAN1 (Gartner et al, 2018;Beijer et al, 2019). Furthermore, a recent report described bi-allelic missense mutations of SPTAN1 in two individuals with hereditary spastic paraplegia (Leveille et al, 2019), which further implicates the gene as important for axonal maintenance.…”

The Spread of Spectrin in Ataxia and Neurodegenerative Disease

“…Human mutations in αII spectrin (SPTAN1) link to early infantile epileptic encephalopathy (EIEE) type 5 (West Syndrome), characterized by refractory seizures, intellectual disability, agenesis of the corpus callosum and hypomyelination [38][39][40][41]. Other SPTAN1 neurological disorders include juvenile onset hereditary motor neuropathy and hereditary spastic paraplegia [28,[42][43][44][45][46].…”