The insertion deletion (ins/del) polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with several psychiatric phenotypes and antidepressant's response. We investigated, in a large cohort of 5,608 controls and subjects suffering from various psychiatric disorders, the frequency of haplotypes and corresponding genotypes combining the 5-HTTLPR and the other serotonin transporter promoter functional variant (rs25531). We showed that rs25531 lies 18 bp 5' to the site where the 43 bp (and not 44 bp as previously described) ins/del defines the 14- and 16-repeat alleles. These polymorphisms should therefore be considered as four alleles instead of a triallelic unique locus. The very rare G-14/G-16 genotype was carried on by only three subjects. These are women with a history of suicide attempt with a psychiatric history strongly suggesting a borderline personality disorder. Two of them have shown a non-response to serotoninergic antidepressant. Interestingly, in one of them was observed a spectacular response after the introduction of bupropion. The genotyping droved our therapeutic approach, by preferring a dopaminergic over a serotoninergic agent. This study highlights the usefulness of studying very rare clinical cases as well as rare variants, in order to deal with the biological heterogeneity of spectral disorders. (c) 2010 Wiley-Liss, Inc.