Identification of an SRY-Negative 46,XX Infertility Male with a Heterozygous Deletion Downstream of SOX3 Gene

Abstract

Background: A male individual with a non-chimeric karyotype of 46,XX is very rare. We explored the genetic aetiology of an infertility male with 46,XX and SRY negative.Methods: The peripheral blood sample was collected from the patient and subjected to a range of genetic testing, including conventional chromosomal karyotyping, short tandem repeat (STR) analysis for chromosome 13, 18, 21, X, Y contained SRY gene, azoospermia factor (AZF) deletion analysis including SRY gene, fluorescence in situ hybridization (FISH) with specific probes for CSP X/CSP Y/SRY, chromosomal microarray analysis (CMA) for genomic copy number variations (CNVs), and whole-genome analysis(WGA) for SNV&InDel variants, and the X chromosome inactivation (XCI) analysis for AR gene.Results: The patient was found to have a 46,XX karyotype. Neither AZFa+b+c nor SRY band was detected in the electrophoresis result. FISH results of both interphase cells with CSPX/CSPY probe and metaphase cells with CSPX/CSPY/SRY probe showed two green fluorescence signals at the centromeres of X chromosomes, but no Y chromosome and SRY fluorescence signal. QF-PCR results showed that the patient had only the AMELX fluorescence peak of the X chromosome but no AMELY and SRY fluorescence peak. All results of the Karyotype, FISH, and STR did not suggest limited Y chimerism. CMA showed he had a heterozygous deletion of about 867 kb in Xq27.1 (hg19: chrX: 138,612,879-139,480,163 bp), located at 104 kb downstream of SOX3 gene, including F9, CXorf66, MCF2 and ATP11C; Meanwhile, whole-genome sequencing also found no SNV&InDel mutation associated with abnormal sex development. 75% X chromosome inactivation was detected.Conclusions: Although the pathogenicity of 46,XX male patients with SRY negative remains unclear, SOX3 expression of the acquired function may be associated with partial testis differentiation. Therefore, copy number variation of SOX3 gene and regulatory region should be performed routinely for these patients.