A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly |
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Authors: | Naseebullah Kakar Ingrid Goebel Shakeela Daud Gudrun Nürnberg Noor Agha Adeel Ahmad Peter Nürnberg Christian Kubisch Jamil Ahmad Guntram Borck |
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Institution: | 1. Department of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan;2. Institute of Human Genetics, University of Ulm, Germany;3. Centre for Applied Molecular Biology (CAMB), Lahore, Pakistan;4. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany;5. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany;6. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany;g Mayo Hospital, Lahore, Pakistan |
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Abstract: | Autosomal recessive intellectual disability is believed to be particularly prevalent in highly consanguineous populations and genetic isolates and may account for a quarter of all non-syndromic cases. Mutations in more than 50 genes have been reported to be involved in autosomal recessive intellectual disability, including TRAPPC9 (MIM 611966), mutations of which have been identified in six families from different geographical origins. We performed a clinical and molecular genetic study of a consanguineous Pakistani family segregating intellectual disability and microcephaly. SNP-array-based homozygosity mapping revealed suggestive linkage to four genomic regions including one on chromosome 8 that contained TRAPPC9. We detected a homozygous TRAPPC9 splice donor site mutation (c.1024+1G>T) that cosegregated with intellectual disability in the family and led to skipping of exon 3 and exons 3 and 4 in blood-derived patient RNA. We have thus identified a novel splice site mutation leading to exon skipping and premature termination of TRAPPC9 translation. These data further suggest that TRAPPC9 mutations –unlike mutations in the vast majority of the known intellectual disability-associated genes– constitute a more frequent cause of autosomal-recessive cognitive deficits, especially when microcephaly is also present. |
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Keywords: | Intellectual disability Mental retardation Microcephaly TRAPPC9 Homozygosity mapping Splice site mutation Exon skipping |
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