A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly

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 i...

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Bibliographic Details
Published in:European journal of medical genetics 2012-12, Vol.55 (12), p.727-731
Main Authors: Kakar, Naseebullah, Goebel, Ingrid, Daud, Shakeela, Nürnberg, Gudrun, Agha, Noor, Ahmad, Adeel, Nürnberg, Peter, Kubisch, Christian, Ahmad, Jamil, Borck, Guntram
Format: Article
Language:English
Subjects:
Base Sequence
Carrier Proteins - genetics
Child
Child, Preschool
Chromosome Mapping
Consanguinity
Exon skipping
Exons
Facies
Female
Homozygosity mapping
Homozygote
Humans
Intellectual disability
Intellectual Disability - genetics
Intercellular Signaling Peptides and Proteins
Lod Score
Male
Medical Education
Mental retardation
Microcephaly
Microcephaly - genetics
Mutation
Pakistan
Pedigree
RNA Splice Sites
Splice site mutation
TRAPPC9
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Summary: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.
ISSN:1769-7212
1878-0849
DOI:10.1016/j.ejmg.2012.08.010