PATERNAL SOMATIC AND GERM-LINE MOSAICISM FOR A SEX-DETERMINING REGIONON 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 (DN A) from peripheral lymphocytes and sperm were analyzed for duplication of the dosage sensitive sex locus (DSS) and for mutations in sex-dete rmining region on Y (SRY). Setting: An academic teaching hospital. Pat ients: A family consisting of mother, father, and five phenotypic daug hters, of which two were 46,XY sex-reversed females. Intervention: Deo xyribonucleic acid (DNA) extraction, polymerase chain reaction (PCR), Southern blotting, dosage densitometry, single-strand conformation pol ymorphism (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 i dentical 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 als o demonstrated the same mosaicism for the T --> G missense mutation. C onclusion: A postembryonic SRY mutation gave rise to paternal mosaicis m for two distinct cell populations (SRY+/SRY-). The presence of a wil d type SRY in the somatic cell line may account for a normal pattern o f male sexual differentiation, whereas the presence of a mutated SRY i n the germ line resulted in two 46,XY sex-reversed offspring. These re sults confirm a proposed mechanism for the condition of recurrent 46,X Y sex-reversed females. (C) 1997 by American Society for Reproductive Medicine.