Should we genotype the sperm of fathers from patients with 'de novo' mutations?

Abstract

In this issue of the European Journal of Endocrinology, Lin et al. report a de novo heterozygous nonsense variant in the PHEX gene in an X-linked hypophosphatemic rickets patient. The authors described a germline mosaicism in the sperm of the unaffected father of the proband, providing the opportunity to discuss the concept of isolated germline mosaicism. In addition to the genetic information passed on from generation to generation, each of us is born with a small number of novel genetic changes -de novo mutations- that occurred either prezygotically or postzygotically. When de novo mutational events occur prezygotically, mutation may pre-exist in a parent who is mosaic but the mutation might be inherited in the zygote and potentially in all cells of the developing offspring resulting in a de novo disease phenotype. Only somatic cells (mainly from blood and skin) are routinely used in genetic analyses, and a hint about possible germline mosaicism can be obtained only if somatic mosaicism is detected, or if more affected siblings are born with an identical de novo variant. There is now a wide range of disorders for which the occurrence of parental germline mosaicism has been reported. Interestingly, Lin et al. analyzed eight different tissues of the proband's father (including sperm), which allowed a conclusive assessment of his mosaicism extension. This study suggests that sperm analysis could more often be performed in our routine genetic screening for germline mosaicism in fathers of patients with apparently de novo mutations.