ClinVar

In 8 children from 5 families from the northwest region of England who manifested a combined deficiency of adaptive immunity (IMD24; 615897), Martin et al. (2014) detected a homozygous G-to-C transversion at the -1 position of intron 17 of the CTPS1 gene (rs145092287) using whole-exome and confirmatory Sanger sequencing. The authors referred to the mutation as IVS18-1G-C and noted its genomic location as position 41475832 on chromosome 1. The mutation resulted in expression of an abnormal transcript lacking exon 18. The mutation was considered deleterious since CTPS1 protein expression could not be detected in lysates of EBV-transformed B cells and T-cell blasts from patients. All parents and unaffected sibs tested were heterozygous carriers. Sequencing of a cohort of 752 healthy individuals from the northwest of England gave an estimated frequency of homozygosity of 1 in 560,000. This frequency represented a more than 10-fold increase compared to the frequency estimated from available exome databases. Whole-exome sequencing data and analysis of polymorphic microsatellite markers in all patients revealed a common region of homozygosity of 1.1 Mb surrounding the mutation. These data indicated a founder effect.