ESPE Abstracts

Background: RSPO1 is an activator of the canonical Wnt signalling pathway by acting as a ligand for LGR4–6 receptors and an a 46,XX individual it represses testicular development. Only three families have been reported in the literature with recessive mutations in RSPO1 and syndromic 46,XX sex-reversal.

Objective and hypotheses: We identified a consanguineous family from Southern Morocco with two sibs presenting with 46,XX testicular and ovotesticular DSD, palmoplantar keratoderma, and hearing impairment. We hypothesised that the phenotype may be due to a recessive loss-of-function mutation involving RSPO1.

Method: We performed exome sequencing with an average coverage of 60× using the Illumina HiSeq2000 Systems. All rare (MAF <0.01) and novel variants were identified and evaluated for there contribution to the phenotype.

Results: Both sibs were SRY-negative. We identified a novel homozygous c.332G>A mutation that is predicted to result in a p.Cys111Tyr amino acid change (ENSP00000348944). Both parents were heterozygous for the mutation and the mutation was not observed in 200 normospermic controls from Morocco. The mutation disrupts an evolutionary conserved residue in the second furin-like repeat and the amino acid change is predicted to be highly deleterious by both SIFT and PolyPhen2.

Conclusion: This is the forth family to be identified with syndromic ovotesticular/testicular DSD carrying a recessive mutation in RSPO1. This highlights the key role that RSPO1 signalling plays in repressing testicular development in XX individuals.

Funding: This work was supported by the ACIP, Institut Pasteur.