DISCUSSION
In this report, we present phenotypically male and female siblings each with the same male karyotype with partial 3p duplication and partial 9p deletion. Their clinical features overlap those associated with 3p duplication and 9p deletion (Table S1). The duplicated 3p and deleted 9p regions are smaller in our patients compared to the common sizes associated with patients reported in the literature, which could account for the milder phenotype in our patients.
The 9p deletion syndrome is associated with DSD. Patients with a distal 9p deletion and a male karyotype, show a wide spectrum of abnormal sex development ranging from females with complete gonadal dysgenesis to males with hypospadias. The critical region for complete gonadal dysgenesis has been localized to the 9p24.3, extending from theDMRT genes to the telomere (Barbaro et al., 2009; Guioli et al., 1998; Veitia et al., 1997) This region is separate from the 9p deletion syndrome critical region (9p22.3-9p23) (Flejter et al., 1998; Veitia et al., 1997). The DMRT genes (DMRT1 , DMRT2 , andDMRT3 ) located at 9p24.3 are considered as gene candidates for gonadal dysgenesis (Muroya et al., 2000). These genes encode for proteins with a DM (doublesex/MAB-3) domain, a zinc-finger-like DNA binding, and are involved in downstream pathways of sex determination (Barbaro et al., 2009). In mice, Dmrt1 is expressed in both germ cells and Sertoli cells of the testis, and has been shown to be essential to maintain testis determination (Raymond, 2000). Recent studies in humans support that haploinsufficiency of DMRT1,associated with 9p deletions, is the most likely explanation of DSD. Macdonald et al. (2018) used a novel approach to repress DMRT1 in the tissue of human fetal testes, and showed DMRT1 repression induces testicular dysgenesis. Furthermore, a recent exome study identified a missense mutation in DMRT1 in a patient with XY sex reversal (Murphy et al., 2015) further supporting that DMRT1 is a candidate gene for XY sex reversal.
It has been shown that haploinsufficiency for DMRT1 results in gonadal dysgenesis and DSD with variable penetrance and expressivity (Quinonez et al., 2013). A review of 88 cases of monosomy 9p with a male karyotype revealed that ~80% (72/88) had genital abnormalities and/or complete gonadal dysgenesis, while ~20% of them had no genital abnormalities. The underlying mechanism of this variability has been unclear. Since a large percentage of 46,XY patients with 9p deletions that had DSD harbored a secondary copy number variation (CNV), the authors hypothesized that abnormal sex development may be due to the presence of a second-hit (CNV or other molecular mechanism) in addition to DMRT1haploinsufficiency. In our study, we did not detect significant CNVs however, regions of AOH were detected with the regions of AOH in patient 2 being larger (3.78% of the entire genome including 62 Mb AOH on chromosome 7) than in patient 1 (2.22% of the entire genome; Figure S2). It may be possible that a homozygous state of a gene or genes in the AOH regions in patient 2 served as a second hit, accounting for her sex reversal phenotype. Alternatively, it may be possible that additional small CNVs or other genetic changes undetectable by CMA account for the difference in sex development between the two patients.
In conclusion, the two patients reported here add to the study of individuals with partial 3p duplication and 9p deletion. Of reported cases, only two have had 46,XY and sex reversal (Fryns et al., 1986; Witters et al., 2004). Our two patients are also of interest as they are a brother and sister with the same genotype defined by karyotype and CMA, but their phenotypes, specifically in regards to sex development and gender identity, are different.