Familial frameshift SRY mutation inherited from a mosaic father with testicular dysgenesis syndrome.
BACKGROUND
The SRY gene encodes a transcription factor responsible for initiating testis differentiation. Mutations in SRY almost always result in XY sex reversal with pure gonadal dysgenesis and an increased risk of gonadal tumor. Most of these mutations are de novo, affecting only one individual in a family. Only a small subset of mutations is shared between a phenotypically normal father and one or more of his affected children. Incomplete penetrance and somatic mosaicism are two hypotheses that may explain a normal phenotype in a father carrying a SRY mutation.


RESULTS
We describe a family with two sisters with XY sex reversal and pure gonadal dysgenesis and a phenotypically normal brother. A novel constitutional frameshift SRY mutation was identified in both sisters and was absent in the brother. The single base pair deletion (c.71delA) led to a premature stop codon in position 60 of the protein, removing entirely the high-mobility group domain and the DNA-binding domain of SRY. The father of the three children presented with hypospadias; cryptorchidism; testicular seminoma and oligoasthenozoospermia, an association termed testicular dysgenesis syndrome (TDS); and the SRY mutation in a mosaic state in the peripheral blood and the tumor.


CONCLUSIONS
This observation of somatic and germinal mosaicism for a SRY mutation may explain the variable penetrance in some familial gonadal dysgenesis. Importantly, the present report is the first one describing the association of SRY mutation in a male with TDS. This suggests that mutations in a sex-determining gene may contribute to the pathogenesis of TDS.
Isidor
Bertrand
B
Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, 9 Quai Moncousu, 44093 Nantes Cedex 1, France.
Capito
Carmen
C
Paris
Françoise
F
Baron
Sabine
S
Corradini
Nadège
N
Cabaret
Blandine
B
Leclair
Marc-David
MD
Giraud
Mathilde
M
Martin-Coignard
Dominique
D
David
Albert
A
Sultan
Charles
C
Le Caignec
Cédric
C
D000293:Adolescent; D002648:Child; D005260:Female; D016368:Frameshift Mutation; D006059:Gonadal Dysgenesis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D051876:Sex-Determining Region Y Protein / Q000235:genetics*
D051876:Sex-Determining Region Y Protein