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.
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Acknowledgements
This study is supported by grants from the Canadian Institute of Health Research (CIHR) (J Michaud, G Rouleau, J-C Lacaille), Réseau de Génétique Médicale Appliquée (RMGA)/Fonds de la Recherche en Santé du Québec (FRSQ) (J Michaud), Genome Canada and Genome Quebec and co-funding by Université de Montréal for the Synapse to diseases (S2D) project (G Rouleau), the Ministry of Health, Labour and Welfare (H Saitsu, N Matsumoto), the Japan Science and Technology Agency (N Matsumoto), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (N Matsumoto), and a Grant-in-Aid for Young Scientist from the Japan Society for the Promotion of Science (H Saitsu). J Michaud is the recipient of a Clinical Investigatorship Award of the CIHR (Institute of Genetics) and of a Senior Scientist Award from FRSQ. G Rouleau holds the Canada Research Chair and a Jeanne-et-J-Louis-Levesque Chair for the Genetics of Brain Diseases. We are grateful for the dedicated work of members of the S2D team (CHUM Notre-Dame Hospital Research Center, Montreal), including management (Claude Marineau and Ronald Lafrenière) and bioinformatics (Edouard Henrion and Ousmane Diallo). We are thankful for the efforts of the members of McGill University and Génome Québec Innovation Centre Sequencing and Bioinformatics groups.
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Hamdan, F., Saitsu, H., Nishiyama, K. et al. Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy. Eur J Hum Genet 20, 796–800 (2012). https://doi.org/10.1038/ejhg.2011.271
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DOI: https://doi.org/10.1038/ejhg.2011.271
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