Commentary to: Fertility potential in 5α-reductase type 2 deficient males

Markouli et al. report the results of a systematic review of the literature where they identified 9 individuals with a detected mutation in the 5α-reductase type 2 enzyme gene that subsequently were able to conceive in their adult life [ ]. This manuscript highlights the importance of early genotyping to confirm diagnosis. Diagnostic workup of patients with differences in sexual development is guided based on phenotype assessment and the tendency is to genotype (gene panel, exome, genome and more recently long-read sequencing) cases with what the clinician interprets as “severe/classic phenotype” or those with possible syndromic features [ ]. Milder phenotype anomalies are generally not studied and rarely end up undergoing genetic sequencing. Variable expressivity and incomplete penetrance generates low genotype/phenotype correlation. Subtle phenotype nuances may not be evaluated in depth and accurate genetic diagnosis can be missed. Clinical impact of a lack or delayed diagnosis affects patient's and families at multiple levels. Recent reports have shown rising positive detection of mutations for milder phenotypes [ ]. Growing understanding of variants of uncertain significance may improve genetic detection in this group of patients. Genotyping milder phenotypes (isolated distal hypospadias) and ideally all cases with suspicion for a difference in sexual development, regardless of severity of the phenotype, will offer the ability to use the genotype as a predictive variable to guide management such as preoperative testosterone for specific reconstructive cases as well as a predictor for surgical outcomes beyond the current indications to guide diagnosis, counseling oncological risk, future fertility potential and future generation recurrence.