Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal

Objective: To determine the etiology for recurrent 46,XY sex reversal in a family with two Swyer siblings. Design: Deoxyribonucleic acid (DNA) from peripheral lymphocytes and sperm were analyzed for duplication of the dosage sensitive sex locus (DSS) and for mutations in sex-determining region on Y (SRY). Setting: An academic teaching hospital. Patients: A family consisting of mother, father, and five phenotypic daughters, of which two were 46,XY sex-reversed females. Intervention: Deoxyribonucleic acid (DNA) extraction, polymerase chain reaction (PCR), Southern blotting, dosage densitometry, single-strand conformation polymorphism (SSCP), and sequencing. Main Outcome Measure: Comparison of control and subject DNA. Results: Deoxyribonucleic acid (DNA) analysis of SRY in genomic DNA from the 46,XY sex-reversed siblings revealed identical missense mutations (T → G) in both sisters. Analysis of the SRY gene in paternal lymphocyte and sperm DNA revealed mosaicism for wild and mutant (T → G) SRY sequences. SRY analysis of sperm DNA also demonstrated the same mosaicism for the T → G missense mutation. Conclusion: A postembryonic SRY mutation gave rise to paternal mosaicism for two distinct cell populations (SRY+/SRY-). The presence of a wild type SRY in the somatic cell line may account for a normal pattern of male sexual differentiation, whereas the presence of a mutated SRY in the germ line resulted in two 46,XY sex-reversed offspring. These results confirm a proposed mechanism for the condition of recurrent 46,XY sex-reversed females.