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Case Reports
, 48 (10), 710-2

XX Males SRY Negative: A Confirmed Cause of Infertility

Case Reports

XX Males SRY Negative: A Confirmed Cause of Infertility

Annalisa Vetro et al. J Med Genet.


Background: SOX9 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 results: We 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.

Conclusions: Our 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.

Conflict of interest statement

Competing interests: None to declare.


Figure 1
Figure 1
Family tree of the two XX brothers and characterisation of the 96 kb triplication region. (A) Pedigree of the family. Asterisks indicate persons for whom the karyotype was known, the arrow indicates the proband, and light blue circles indicate the copy number of the 96 kb sex reversal critical region. (B) Array comparative genomic hybridisation (CGH) profile (180K, Agilent Technologies, Santa Clara, California, USA) of the whole chromosome 17 of the proband (left), the 17q24.3 region of the proband (right), and one of his healthy sisters (middle). The triplication is indicated by a shadowed area containing three spots with an average log2 ratio of 1.2. (C) Quantitative PCR (qPCR) with specific primer pairs (supplementary table 3). Affected subjects (P1 and P2), one sister (S) and the mother (M), female (CTRL F) and male (CTRL M) controls were analysed. The relative quantitation (RQ) of copy number is indicated on the y axis. RQ of 1 indicates a normal number of copies; RQ of 2 in P1 and P2 shows the presence of a triplication. Altogether array CGH and qPCR analysis defined the proximal breakpoint of the triplication from 67018227 bp (normal) to 67018939 bp (triplicated) and the distal breakpoint from 67114737 bp (triplicated) to 67119234 bp (normal). Genomic positions are referred to the Human Genome March 2006 (NCBI 36, hg18 assembly). (D) SOX9 and its 1.98 Mb upstream region and a schematic illustration of duplications reported by Kurth et al, 2009 (blue bars), Cox et al, 2011 (green bar), and the triplication observed in the present family (orange bar). Minimal critical region for brachydactyly–anonychia (Kurth et al, 2009) is also shown (blue dashed bar).

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