Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 20, Issue 7, Pages 796-800Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2011.271
Keywords
intellectual disability; epilepsy; SPTAN1; pontocerebellar atrophy
Funding
- Canadian Institute of Health Research (CIHR)
- Reseau de Genetique Medicale Appliquee (RMGA)/Fonds de la Recherche en Sante du Quebec (FRSQ)
- Genome Canada
- Genome Quebec
- Universite de Montreal for the Synapse
- Ministry of Health, Labour and Welfare
- Japan Science and Technology Agency
- Japan Society for the Promotion of Science
- CIHR (Institute of Genetics)
- FRSQ
- Grants-in-Aid for Scientific Research [22689011, 24118001] Funding Source: KAKEN
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Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the alpha-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 alpha/beta 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. European Journal of Human Genetics (2012) 20, 796-800; doi: 10.1038/ejhg.2011.271; published online 18 January 2012
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