title: Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy.
abstract: Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the α-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the α/β spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants.
authors.affiliation: Centre of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du CHU Sainte-Justine, Montréal, Quebec, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Décarie
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis / Q000379:methods; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D006580:Genetic Carrier Screening; D005820:Genetic Testing; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009849:Olivopontocerebellar Atrophies / Q000175:diagnosis / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011859:Radiography; D017384:Sequence Deletion; D014162:Transfection; D013049:Spectrin
chemical_list: D002352:Carrier Proteins; D008840:Microfilament Proteins; D013049:Spectrin