46, XY gonadal dysgenesis: new <i>SRY</i> point mutation in two siblings with paternal germ line mosaicism

<jats:p>Stoppa‐Vaucher S, Ayabe T, Paquette J, Patey N, Francoeur D, Vuissoz J‐M, Deladoëy J, Samuels ME, Ogata T, Deal CL. 46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.</jats:p><jats:p>Familial recurrence risks are poorly understood in cases of <jats:italic>de novo</jats:italic> mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the <jats:italic>SRY</jats:italic> gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same <jats:italic>SRY</jats:italic> mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type <jats:italic>SRY</jats:italic> sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type <jats:italic>SRY</jats:italic> sequence strongly suggesting paternal Y‐chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.</jats:p>