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

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.

Clinical features and early diagnosis of typhoid fever emphasizing usefulness of detecting mesenteric lymphadenopathy with ultrasound as diagnostic method.

Typhoid fever is endemic in Pakistan. Most patients are children. As the symptoms and signs are often unspecific, it is difficult to diagnose typhoid fever without blood culture. We retrospectively reviewed 51 cases of typhoid fever who were all admitted from 1 June through 31 August 2002. Sixteen cases were positive by blood culture and confirmed as typhoid fever. All cases had Salmonella typhi. Although 16 cases were culture-negative, they were clinically diagnosed as typhoid fever. The remaining 19 cases were clinically diagnosed without blood culture. The clinical features of the culture-confirmed cases were more severe than the culture-negative cases. Mesenteric lymphadenopathy was very frequently detected with ultrasonography, in both culture-confirmed and culture-negative cases. The rates of detecting mesenteric lymphadenopathy were 69% and 63%, respectively. Meanwhile, the rate in non-typhoid fever patients was 5.5%. It was considered that detecting mesenteric lymphadenopathy with ultrasonography was very useful in the diagosis of typhoid fever in endemic areas.