title: 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 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.
authors.affiliation: Department of Biotechnology and Informatics, BUITEMS, Quetta, Pakistan.
authors.forename: Naseebullah
authors.initials: N
authors.lastname: Kakar
authors.forename: Ingrid
authors.initials: I
authors.lastname: Goebel
authors.forename: Shakeela
authors.initials: S
authors.lastname: Daud
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Noor
authors.initials: N
authors.lastname: Agha
authors.forename: Adeel
authors.initials: A
authors.lastname: Ahmad
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Jamil
authors.initials: J
authors.lastname: Ahmad
authors.forename: Guntram
authors.initials: G
authors.lastname: Borck
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003241:Consanguinity; D005091:Exons; D019066:Facies; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008126:Lod Score; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D022821:RNA Splice Sites
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D022821:RNA Splice Sites; C503887:TRAPPC9 protein, human