XX males SRY negative: a confirmed cause of infertility

• Published in: Journal of medical genetics Vol. 48; no. 10; pp. 710 - 712
• Main Authors: Vetro, Annalisa, Ciccone, Roberto, Giorda, Roberto, Patricelli, Maria Grazia, Della Mina, Erika, Forlino, Antonella, Zuffardi, Orsetta
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.10.2011; BMJ Publishing Group; BMJ Publishing Group LTD; BMJ Group
• Series: Communications
• Subjects: Azoospermia - genetics; Biological and medical sciences; Birth control; Chromosome Mapping; Comparative Genomic Hybridization; Female; Fundamental and applied biological sciences. Psychology; Gene Duplication; General aspects. Genetic counseling; Genes; Genes, sry; Genetics of eukaryotes. Biological and molecular evolution; Gynecology. Andrology. Obstetrics; Heart attacks; Humans; Infertility; Male; Males; Medical genetics; Medical sciences; Middle Aged; Molecular and cellular biology; Mutation; Pedigree; Real-Time Polymerase Chain Reaction; Reproduction; Sex Chromosome Aberrations; Sex Chromosome Disorders - genetics; SOX9 Transcription Factor - genetics; Sterility. Assisted procreation; Human; Genetics; Male; Sterility
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2011-100036

BackgroundSOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility.Methods and resultsWe report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative.ConclusionsOur results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background.