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Am J Med Genet A. 2018 Dec;176(12):2768-2776. doi: 10.1002/ajmg.a.40628. Epub 2018 Dec 11.

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

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Office of the Clinical Director, NHGRI, and NIH Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, Maryland.
RainDance Technologies, Inc., Billerica, Massachusetts.
Neurodevelopmental and Behavioral Phenotyping Service, Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Neurology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.


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.


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


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