Compound heterozygosity for a large CNV deletion and a rare missense mutation in the FSTL5 gene of a patient affected by schizophrenia.

Although copy number variations (CNVs) represent convincing risk factors in schizophrenia (SC), their presence also in unaffected individuals indicates that additional genetics and/or environmental factors are likely implicated in the development of the disease, as exemplified by the two-hit hypothesis. For instance, the second hit might be a point mutation affecting the same gene. In a genome-wide CNV analysis of an Italian SC cohort we have identified a patient with an heterozygous large deletion encompassing the FSTL5 gene and causing the loss of nearly all the coding sequence. Sequencing of all the FSTL5 coding exons of the patient revealed a T>C transition leading to the M453T mutation. This mutation was predicted to be gamaging either by Polyphen and MutationTaster software. As the M453T mutation was not reported in the dbSNP132 database, we screened the DNA of 164 SC patients and 246 controls for the presence of the mutation. The M453T substitution was identified in heterozygosity in a second patient and in one control. Given its rarity, the occurrence of the M453T substitution in a SC patient carrier of a FSTL5 deletion suggests that this missense mutation could contribute to the clinical phenotype, likely acting through a recessive effect disclosed by the hemizygous condition. The FSTL5 gene encodes for a secreted glycoprotein with partial homology to follistatin, a well-known modulator of activin and other TGF-β superfamily members. Although functional studies would be required, the co-occurrence in the same SC patient of two rare alterations in the FSTL5 gene (a large CNV deletion and the M453T substitution) suggests that these two events may be important for the development of the disorder. Thus, our data supports the two-hit model as one of the mechanisms implicated in SC and highlights FSTL5 as a candidate gene in the etiopathogenesis of the disease.