NIH Research Festival
Background: Patients with mutations in Non-erythrocytic Alpha Spectrin 1 (SPTAN1) have very similar reported phenotypes including intractable seizures, intellectual disability, and reduced brain volume. Two unrelated patients evaluated by the Undiagnosed Diseases Program were diagnosed with de novo mutations in SPTAN1. These patients do not conform to the previously published phenotype; neither has epilepsy, which was previously considered a hallmark symptom with SPTAN1 mutations. We are interested in understanding factors that may differentiate phenotypes with and without epilepsy. Methods: Genomic DNA was collected from the patients and unaffected family members for whole exome sequencing. Sequence data was aligned to a human reference genome and variants were filtered based on predicted deleteriousness, rarity, and Mendelian segregation. In both patients presented here, novel de novo mutations in SPTAN1 were detected and verified. Digital droplet polymerase chain reaction quantified SPTAN1 expression. Results: Patient 1 presented with ataxia, global developmental delay, small cerebellum, and hypotonia. He was heterozygous for a de novo intronic missense mutation in SPTAN1 that leads to a premature splice acceptor site and the addition of five amino acids to the SPTAN1 protein. Patient 2 presented with intellectual disability, developmental delay, microcephaly, and multiple congenital anomalies and had a heterozygous de novo nonsense mutation. Preliminary expression results indicate that both patients express wild type SPTAN1 at roughly half the amount seen in control fibroblasts with detectable expression of their mutant alleles. Summary: We report two cases of disease caused by mutations in SPTAN1 suggesting greater phenotypic heterogeneity than was previously reported.
Scientific Focus Area: Genetics and Genomics
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