Context: The SRY gene encodes a transcription factor responsible for initiating testis differentiation. Mutations in SRY almost always result in XY sex-reversal with pure gonadal dysgenesis and an increased risk of gonadal tumour. Most of these mutations are de novo affecting only one individual in a family. Only a small subset of mutations is shared between a phenotypically normal father and one or more of his affected children. Incomplete penetrance and somatic mosaicism are two hypotheses that may explain a normal phenotype in a father carrying a SRY mutation.

Patients-Results: We describe a family with two sisters with XY sex-reversal and pure gonadal dysgenesis and a phenotypically normal brother. A novel constitutional frameshift SRY mutation was identified in both sisters and was absent in the brother. The single base-pair deletion (c.71delA) led to a premature stop-codon in position 60 of the protein removing entirely the HMG domain and the DNA-binding domain of SRY. The father of the three children presented with hypospadias, cryptorchidism, testicular seminoma and oligoasthenozoospermia, an association termed testicular dysgenesis syndrome (TDS), and the SRY mutation in a mosaic state in the peripheral blood and the tumour.

Conclusions: This observation of somatic and germinal mosaicism for a SRY mutation may explain the variable penetrance in some familial gonadal dysgenesis. Importantly, the present report is the first one describing the association of SRY mutation in a male with TDS. This suggests that mutations in a sex-determining gene may contribute to the pathogenesis of TDS.