Background Cryptorchidism or failure of testicular descent is the most common genitourinary birth defect in males. While both the insulin-like peptide 3 (INSL3) and its receptor, relaxin family peptide receptor 2 (RXFP2), have been demonstrated to control testicular descent in mice, their link to human cryptorchidism is weak, with no clear cause–effect demonstrated.
Objective To identify the genetic cause of a case of familial cryptorchidism.
Methods We recruited a family in which four boys had isolated bilateral cryptorchidism. A fourth-degree consanguineous union in the family was reported. Whole exome sequencing was carried out for the four affected boys and their parents, and variants that segregated with the disorder and had a link to testis development/descent were analysed. Functional analysis of a RXFP2 variant in cell culture included receptor localisation, ligand binding and cyclic AMP (cAMP) pathway activation.
Results Genomic analysis revealed a homozygous missense variant in the RXFP2 gene (c.1496G>A .p.Gly499Glu) in all four affected boys and heterozygous in both parents. No other variant with a link to testis biology was found. The RXFP2 variant is rare in genomic databases and predicted to be damaging. It has not been previously reported. Functional analysis demonstrated that the variant protein had poor cell surface expression and failed to bind INSL3 or respond to the ligand with cAMP signalling.
Conclusion This is the first reported genomic analysis of a family with multiple individuals affected with cryptorchidism. It demonstrates that recessive variants in the RXFP2 gene underlie familial cryptorchidism and solidifies the link between this gene and testicular descent in humans.
- undescended testis
- exome sequencing
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KA and RK contributed equally.
Contributors KA carried out genomic analysis and coordinated the study. RK was the treating clinician and compiled all clinical notes. GR handled DNA and carried out genomic analysis. KB carried out bioinformatic analysis. SB carried out variant functional testing under supervision of RAB. MAM was the treating surgeon and contributed to clinical notes. AS oversaw the study. KA, RK, GR and RAB co-wrote the manuscript.
Funding Genomics work and GR are supported by National Health and Medical Research Council of Australia (NHMRC) program grant . KLA is supported by an NHMRC project grant . AHS is supported by a NHMRC fellowship . Research at the Florey was supported by NHMRC project grants  and  and the Victorian Government Operational Infrastructure Support Program. RADB is supported by an NHMRC Research Fellowship .
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available upon reasonable request.
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