ABSTRACT
Background
When the SRY gene is present in a 46,XX fetus, some degree of testicular development is expected. Our laboratory performed prenatal genetic testing for a fetus that had screened positive for Y chromosome material by noninvasive prenatal screening (NIPS) but that had apparently typical female development by ultrasound imaging. The aim of this study was to determine the clinical relevance of the NIPS results.
Methods
We analyzed fetal material obtained via amniocentesis procedure by G‐banding, microarray, and fluorescence in situ hybridization (FISH). Optical genome mapping (OGM) was also performed.
Results
G‐band analysis revealed a normal 46,XX karyotype. Microarray and FISH analyses together detected an SRY+ gain of 5.7 Mb from terminal Yp that was translocated to terminal Xq, with a loss of 1.6 Mb from terminal Xq. The final karyotype was 46,X,der(X)t(X;Y)(q28;p11.2). Prenatal ultrasound and postnatal physical examination revealed apparently typical female genitalia. The Xq deletion encompassed a gene, IKBKG, that is sensitive to loss of function, suggesting that preferential inactivation of the derivative X chromosome allowed for typical female development. OGM software did not directly identify this translocation.
Conclusion
This case demonstrates how the SRY gene may be present in a 46,XX biological female without differences of sexual development.
Keywords: differences of sexual development, ovotesticular, sex reversal, X inactivation
When the SRY gene is present in a 46,XX fetus, some degree of testicular development is expected. Our laboratory detected an SRY+ derivative X chromosome resulting from a translocation between Xq28 and Yp11.2 in an apparently typical female neonate. This case demonstrates how the SRY gene may be present in a 46,XX biological female without differences of sexual development.
1. Introduction
The sex‐determining region Y, or SRY (OMIM 480000), is the Y chromosome gene that initiates testicular development in the germinal ridge cells of the embryo. If the SRY gene is present in an individual with two X chromosomes, as can occur following an X‐Y translocation, testicular development is expected to occur. In most cases, SRY+ 46,XX individuals develop bilateral testes and become biological males, though with consequent infertility (Cohn, Scherer, and Hamosh 2020; Delot and Vilain 2003 [updated 2022]). In fewer cases, the SRY+ 46,XX individual develops a mixture of testicular and ovarian tissue (Syryn, Van De Vijver, and Cools 2023). These two phenotypes are referred to as 46,XX testicular difference of sexual development (DSD), and 46,XX ovotesticular DSD, respectively (Delot and Vilain 2021). Interestingly, the presence of the SRY gene in typical 46,XX biological females has only been reported twice, and standard cytogenetic testing such as G‐banding and fluorescent in situ hybridization (FISH) analyses was only available in the most recent report (Politi et al. 2024; Sharp et al. 2004).
We recently received an amniotic fluid sample for which the indication for testing was a noninvasive prenatal screening (NIPS). The result was suggestive of an atypical finding that was outside the scope of screening but involved the Y chromosome. Additional details regarding the suspected Y chromosome abnormality were not available. Maternal age was in the early 30s. On prenatal ultrasound imaging at 16 weeks gestation, fetal genitalia was most consistent with female genitalia. We analyzed fetal chromosomes and DNA extractions isolated from the amniotic fluid using a combination of FISH, G‐banded karyotyping, and single nucleotide polymorphism (SNP) microarray. We also performed optical genome mapping (OGM) on a research basis during the validation of OGM in our laboratory. Results of all testing were consistent with an SRY+ derivative X chromosome in an otherwise typical female fetus.
2. Methods
2.1. Ethical Compliance
To ensure the privacy of the affected individual and their family, all clinical and personal information has been anonymized. Our institution's IRB office was consulted, and they determined IRB review was not required as this is an anonymized report of a single patient. Informed consent could not be obtained because the family was lost to follow‐up. To ensure the privacy of the affected individual and their family, all clinical and personal information has been anonymized.
2.2. Maternal Cell Contamination Studies
Short tandem repeat (STR) sequences were analyzed in maternal blood and cultured amniocytes using the GlobalFiler PCR Amplification Kit (Thermo Fisher Scientific). A total of 24 chromosomal loci were amplified for STR analysis, and five informative loci were identified.
2.3. Karyotyping
G‐banded karyotyping was performed on cultured amniotic fluid cells. Cells were grown and stained on coverslips. The number of chromosomes was assessed in 15 metaphases across 15 colonies, and five metaphases were analyzed at a 525‐band level.
2.4. Fluorescent In Situ Hybridization (FISH)
Initial analysis was performed with an interphase aneuploidy FISH panel that enumerates copy number of chromosomes 13, 18, 21, X and Y, using probes for RB1 (Oxford Gene Technology, Kidlington, United Kingdom), D18Z1 (Oxford Gene Technology), DYRK1A/KCNJ6/DSCR8 (Oxford Gene Technology), DXZ1 (Oxford Gene Technology), and DYZ3 (Abbott Molecular, Des Plaines, United States), respectively. Follow‐up metaphase FISH analysis was performed with probes for SRY (Abbott Molecular), SHOX (Oxford Gene Technology), the X centromere (DXZ1, Oxford Gene Technology), and Yq12 satellite region (DYZ1, Abbott Molecular).
2.5. Microarray
DNA for microarray analysis was extracted from cultured amniocytes by isopropanol precipitation using Puregene reagents (Qiagen, Hilden, Germany). Microarray analysis was performed using the Infinium Assay with the Illumina CytoSNP‐850Kv1.2 BeadChip platform. The chip contained approximately 850,000 genome‐wide SNPs, with an overall average probe spacing of 1.8 kb and an average effective resolution of 18 kb. Microarray data were analyzed against the reference genome GRCh37/hg19 using Illumina GenomeStudio V2011.1 software.
2.6. Optical Genome Mapping (OGM)
High molecular weight DNA for OGM analysis was extracted from cultured amniocytes using Bionano Prep SP Amnio and CVS Culture DNA Isolation Protocol (Bionano Genomics, San Diego, United States). Images of fluorescently labeled DNA molecules were collected sequentially across nanochannel arrays on a Saphyr instrument manufactured by Bionano Genomics. An 800Gbp throughput target was set for data collection to achieve greater than 150× coverage of the genome. OGM analysis was performed using Bionano Access software (version 1.7) against reference genome GRCh37/hg19 according to the manufacturer's recommendation.
3. Results
Results from the aneuploidy FISH panel were consistent with a typical XX fetus, with two X chromosome centromeres detected in all 50 cells and no evidence of aneuploidy involving chromosomes 13, 18, or 21. Chromosome analysis by G‐banding was consistent with the aneuploidy FISH panel results, revealing an apparently normal female karyotype (46,XX) in all 15 metaphases examined (Figure 1a). A maternal cell contamination study showed no evidence of maternal cells in the sample tested.
FIGURE 1.
(a) Partial G‐banding karyotype of X chromosomes from amniotic fluid cells. The homologous X chromosomes were indistinguishable by G‐banding. (b) Schematic representation of X chromosomes with a cryptic, unbalanced translocation between X and Y. The gained Y material containing PAR1 and SRY localized to Xqter of the derivative X, replacing PAR2. (c) Prenatal microarray results for the Y chromosome. (d) Prenatal microarray results for the X chromosome. (e) Metaphase FISH for SRY (red probe) and the X centromere (green probe). (f) Metaphase FISH for the pseudoautosomal gene SHOX (red probe) and the X centromere (blue probe). Der(X), derivative X chromosome; PAR1, pseudoautosomal region 1; PAR2, pseudoautosomal region 2; pter, terminus of the p arm; qter, terminus of the q arm.
While the aneuploidy FISH panel and karyotyping did not reveal any chromosomal abnormalities, microarray analysis did detect three copy number variants across the sex chromosomes. Specifically, microarray detected (1) a terminal gain of 2.6 Mb of DNA from pseudoautosomal region 1 (PAR1) (chrX:60,814–2,693,175), (2) a gain of 3.1 Mb from the short arm of chromosome Y (chrY:2,655,180–5,756,210), and (3) a terminal deletion of 1.6 Mb from the long arm of chromosome X (chrX:153,626,533–155,236,747). It seemed likely that the two gains detected by microarray comprised a single event: a terminal gain of 5.7 Mb from the short arm of chromosome Y (Ypter‐Yp11.2) (Figure 1b–d). However, microarray could not inform or determine how the gains and losses were arranged structurally.
To clarify our microarray results, metaphase FISH was performed for the SRY and SHOX loci, at Yp11.2 and PAR1 (Xp22.33/Yp11.32), respectively. FISH detected one copy of SRY at the terminus of one copy of Xq (Figure 1e). The SHOX gene was present in three copies: one at the terminus of Xp on each homologous X chromosome, and one at the terminus of Xq on the derivative X chromosome (Figure 1f). Overall, our testing indicated that the fetus carried a cryptic, unbalanced translocation between Xq28 and Yp11.2, resulting in an SRY+ derivative X chromosome. A terminal gain of 5.7 Mb from Ypter‐Yp11.2 was situated at the site of a terminal loss of 1.6 Mb from Xq28‐Xqter. The genes encompassed by the Yp gain and Xq loss are displayed in Table 1. The derivative X was found in all cells analyzed. The rearrangement was reported as pathogenic, and the karyotype was revised to 46,X,der(X)t(X;Y)(q28;p11.2).
TABLE 1.
Gene–phenotype associations of the derivative X chromosome.
Gene | Inheritance | Phenotype |
---|---|---|
Gain of 5.7 Mb from Ypter‐p11.2 | ||
SHOX |
PR PD |
Langer mesomelic dysplasia Leri‐Weill dyschondrosteosis |
SRY |
XLD YL |
46,XX sex reversal 46,XY sex reversal |
Deletion of 1.6 Mb from Xq28‐qter | ||
RPL10 | XLR | Intellectual developmental disorder |
TAFAZZIN | XLR | Barth syndrome |
ATP6AP1 | XLR | Immunodeficiency 47 |
GDI1 | XLD | Intellectual developmental disorder |
FAM50A | XLR | Intellectual developmental disorder |
LAGE3 | XLR | Galloway‐Mowat syndrome 2 |
G6PD | XL | Hemolytic anemia |
IKBKG | XLD | Incontinentia pigmenti |
DKC1 | XLR | Dyskeratosis congenita |
F8 | XLR | Hemophilia A |
RAB39B | XLR | Intellectual developmental disorder |
CLIC2 | XLR | Intellectual developmental disorder |
TMLHE | XLR | Autism susceptibility |
Note: Gene contents of the Yp gain and Xq loss were determined using the GeneScout website (https://genescout.omim.org/). Genes and phenotypes displayed in bold indicate those that are sensitive to gains (for the Yp region) or losses (for the Xq region).
Abbreviations: PD, pseudoautosomal dominant; PR, pseudoautosomal recessive; XL, X‐linked; XLD, X‐linked dominant; XLR, X‐linked recessive; YL, Y‐linked.
After prenatal genetic testing revealed an SRY+ derivative X chromosome, a follow‐up analysis of the developing fetus' phenotypic sex was performed. Prenatal ultrasound imaging at 35 weeks indicated typical female genitalia without any abnormalities. Postnatal physical examination indicated a healthy female neonate. Typical female external genitalia were noted and female sex was assigned at birth.
As part of our laboratory's clinical validation of OGM, we analyzed DNA from cultured amniocytes from this case. An expected advantage of OGM is the ability to detect chromosomal rearrangements using a single test that would otherwise require multiple platforms (i.e., G‐banded karyotyping, FISH, and/or microarray). Surprisingly, OGM Access Software did not directly detect this X‐Y translocation, instead only calling the 1.6 Mb loss from Xq28. After consulting with the manufacturer, we learned that the translocation could be found in our data by manual inspection, but the translocation could not be identified by the analysis software using current algorithms and filter settings (Figure S1). The data from this rare case is now available as a control during the development of future software releases by the manufacturer.
4. Discussion
The presence of the SRY gene in a 46,XX human embryo is expected to cause testicular cell development. However, the chromosomal location of SRY was unusual in this case, as it was not translocated from Yp to Xp but instead from Yp to Xq. Additionally, there was a terminal loss of 1.6 Mb from Xq28, deleting several disease‐associated genes. Therefore, we considered whether this unbalanced translocation might result in complete inactivation of the SRY+ derivative X chromosome, thereby silencing the SRY gene and allowing for typical female development in an SRY+ individual.
To better predict the effect of this translocation on fetal development, we analyzed the genes that were lost and gained on the derivative X chromosome. Importantly, the Xq deletion encompassed two genes sensitive to loss of function: IKBKG and F8. IKBKG is associated with X‐linked dominant incontinentia pigmenti (IP), a progressive neuroectodermal dysplasia that primarily affects females. Skin findings are usually the first sign of IP, beginning with blisters in the first postnatal months, followed by a rash, and then distinctive patterns of hyperpigmentation by approximately 6 months of age. Some individuals with IP also experience neurological symptoms such as developmental delay, seizures, and intellectual disability beginning in the 1st year of life. Pathogenic IKBKG variants in males usually cause embryonic lethality (Fusco et al. 2008; Smahi et al. 2000). While certain loss of function variants in IKBKG are known to cause IP in females, in particular a recurrent 11.7 kb deletion of exons 4–10, full gene deletions have not been reported in association with IP (Scheuerle and Ursini 1999 [updated 2017]). It may be that the loss of the entire IKBKG locus is devastating to cells during early embryonic development, causing completely skewed X inactivation in females and protection against IP. Because the entire IKBKG locus is deleted in the case presented here, we did not expect the child to present with IP. Of note, no skin findings were reported at birth.
The second gene deleted from Xq28 that was sensitive to loss of function was F8, associated with X‐linked recessive hemophilia A (OMIM 306700). This clotting disorder is typically seen in males, though females can show mild effects (Konkle and Nakaya Fletcher 2000 [updated 2023]). Whole gene deletions of F8 are not often reported in association with hemophilia A except in females with a second F8 mutation on their homologous X chromosome (Rost et al. 2013; Song et al. 2011). Therefore, we did not expect the individual reported here to present with hemophilia unless there was a pathogenic variant in their second F8 allele.
Among the loci that were gained on the derivative X chromosome, SRY was the only gene sensitive to gains. As mentioned previously, gain of SRY is associated with 46,XX sex reversal (OMIM 400045), presenting as either 46,XX testicular DSD or 46,XX ovotesticular DSD. However, we suspected that skewed X inactivation might completely silence SRY in this case and allow for typical female development. Our hypothesis was later supported by phenotypic findings: prenatal ultrasound at 35 weeks and postnatal physical examination both reported typical female external genitalia.
There have been two other translocations between Xq and Yp reported in the literature. In the first case, Margarit et al. (2000) described a t(X;Y)(q28;p11.3) in an individual presenting with “true hermaphroditism,” or what is now called 46,XX ovotesticular DSD. G‐banding revealed a 46,XX chromosomal complement while FISH revealed a derivative X with Yp material present at terminal Xq. Telomeric Xq sequences were missing from the derivative X per FISH analysis, though the amount of Xq material that was deleted was not determined. Y chromosome material was analyzed by PCR at sequence‐tagged sites, revealing that the Yp translocation breakpoint occurred at Yp11.3. That affected individual was born with male external genitalia along with hypospadias and raised as male for the first 2 years of life. However, sexual ambiguities led to genetic testing and the identification of a 46,XX karyotype. Sex change was subsequently opted for and gender‐confirming surgery was performed. It is unknown what genes were lost from terminal Xq and whether IKBKG was involved. It can be hypothesized that the unbalanced translocation was deleterious enough to cause some skewing of X inactivation, but that enough gonadal cells expressed SRY on an active X to cause some testicular development. Another possibility is that the translocation caused completely skewed X inactivation, but the SRY gene escaped X inactivation in some gonadal cells.
In the second reported Xq‐Yp translocation, an SRY+ der(X) t(X;Y)(q28;p11.2) was detected in four apparently normal females across three generations of the same family (Politi et al. 2024). This recent report by Politi et al. (2024) was like ours in that the proband was identified after NIPS indicated abnormal presence of Y material in an XX fetus. The Yp gain and Xq loss were larger in the Politi et al. case than in our case: Politi et al. (2024) detected a 9 Mb Yp gain and 6.3 Mb Xq loss, while we detected a 5.7 Mb Yp gain and a 1.6 Mb Xq loss. The authors postulated that skewed X inactivation allowed the SRY gene to be completely silenced in the four females; this theory was supported by X inactivation studies in lymphocytes. We suspect that skewed X inactivation is also involved in our case, though X inactivation studies were not performed. This report by Politi et al. together with our current case, demonstrates how NIPS can uncover unexpected cases of SRY+ derivative X chromosomes in 46,XX fetuses that have apparently typical female development.
It is important to remember that skewed X inactivation is not complete, as ~15% of genes do escape inactivation and are expressed from the inactive X chromosome to some degree. Of those genes that escape X inactivation, up to 50% are reported to come from distal Xp with only a small percent coming from Xq (Cohn, Scherer, and Hamosh 2020). While this case has a full gene deletion of IKBKG that may drive skewed X inactivation, the SRY gene might still escape X inactivation and cause some degree of testicular development. It is therefore currently unknown whether low‐level expression of SRY may have impacted gonadal development to some degree in this case. Long‐term follow‐up through puberty would be required to rule out this possibility. Of note, it is interesting that several distal Xp regions are known to escape X inactivation while Xq regions rarely do. This may explain why SRY tends to cause complete sex reversal when translocated onto the Xp arm but not when translocated onto the Xq arm.
While Xp‐Yp translocations are a well‐known cause of testicular development in 46,XX individuals, there is one report of SRY+ Xp‐Yp translocations in phenotypic females (Sharp et al. 2004). The Sharp et al. report began with two possibly unrelated probands that presented with 46,XX ovotesticular DSD. Familial studies were performed, and the derivative X chromosomes were surprisingly detected in the parents of both probands: in the father of one proband and in the mother of the second proband. In the second case, the mother's sister (i.e., maternal aunt of the proband) also showed evidence of carrying the SRY+ derivative X. Genetic testing was performed using microsatellite markers, single‐stranded conformation polymorphism analysis, and Southern blotting. Standard cytogenetic testing such as G‐banding and FISH analysis was not performed. The findings by Sharp et al. suggest that some SRY+ derivative X chromosomes might be passed down through families by fertile individuals and cause variable phenotypes in different generations.
The mechanism of translocation between Xq and Yp in our case remains unclear. It was hypothesized by Margarit et al. (2000) that an Xq‐Yp translocation could be facilitated by a paternal Y chromosome inversion, leading to atypical meiotic recombination. However, this possibility could not be tested by Margarit et al. or by our own laboratory because paternal samples were not made available for testing. Regarding developmental timing, the original recombination event most likely occurred during male meiosis. While it is possible that the recombination event occurred during male mitosis, making the male a mosaic carrier, homologous recombination with crossing over is known to occur much more frequently in meiosis than mitosis (Moynahan and Jasin 2010). Therefore, it seems likely that the translocation was a de novo event during the meiosis of the proband's father. Interestingly, it is also possible that the proband inherited the translocation from a carrier mother, as a similar Xq‐Yp translocation was recently found to transmit through three generations of a maternal lineage (Politi et al. 2024). This phenomenon may be underappreciated in the medical literature due to limited genetic testing on “normal” individuals but may become more widely reported with the advent of NIPS. Of note, the parents in our case could not be tested for carrier status as they were lost to follow‐up after delivery.
Our discussion has thus far focused on X‐Y translocations, but there are other situations where the SRY gene can exist in phenotypic females. The main example is 46,XY complete gonadal dysgenesis, also known as Swyer syndrome, where female development occurs with a 46,XY chromosomal complement. While most of these cases do not have a known genetic explanation, 10%–20% of cases are caused by a loss‐of‐function mutation in the SRY gene. Other known causes include mutations to NR5A1 and MAP3K1 (Elzaiat, McElreavey, and Bashamboo 2022; Rudnicka et al. 2024). Individuals with 46,XY complete gonadal dysgenesis are born with female external genitalia and internal female structures. Streak gonads are present and have the potential for gonadoblastoma. Lack of hormone production from the streak gonads causes delayed puberty and primary amenorrhea (Narita et al. 2023; Raveendran et al. 2019). Hormone replacement is recommended, allowing for the induction of puberty and increased bone density. Bilateral gonadectomy is also recommended to prevent eventual malignancy. Pregnancy can occur in affected individuals if they are provided with ova donation and hormone replacement (King and Conway 2014). In contrast to 46,XY complete gonadal dysgenesis, a phenotypic female may also carry SRY if they have a defect in an androgen production gene or the androgen receptor gene (Nunes et al. 2014; Wisniewski et al. 2019). A distinguishing feature between 46,XY complete gonadal dysgenesis versus an androgen production or action defect is that individuals with 46,XY complete gonadal dysgenesis have Müllerian structures, while individuals with a defect in androgen production or action do not have a uterus or fallopian tubes (Domenice et al. 2000; Mendonca et al. 2010). In addition to these examples, the SRY gene can also be found in phenotypic females with 45,X/46,XY mosaicism (i.e., Turner syndrome), or the rare 46,XX/46,XY chimerism (Binkhorst, de Leeuw, and Otten 2009; Lau and Fung 2020). In general, all these examples differ from our present case because the entire Y chromosome is present in the phenotypic females, rather than a small portion of Yp containing the SRY gene. Also, SRY is inactivated by different mechanisms. Even so, these other cases of phenotypic females harboring the SRY gene provide insights into the types of developmental abnormalities that might be expected and what treatments might be beneficial.
Limitations of our study include the absence of detailed phenotypic information and the lack of X inactivation studies. This family was lost to follow‐up after delivery; further phenotypic descriptions were not possible and additional testing, such as postnatal karyotyping and parental testing, could not be performed. Even so, the phenotypic data presented here provides important evidence of typical female development in an SRY+ individual. Regardless of the amount of phenotypic data collected at this early timepoint, we would still be unable to predict later sexual development due to the unknown karyotype of the gonadal tissue. The full effect of the SRY+ derivative X chromosome will not be known until adolescence when this individual might present with delayed puberty and amenorrhea. Regarding X inactivation studies, our laboratory does not currently perform such assays, and the major reference laboratories declined to process prenatal samples, even for research purposes. However, even if an amniotic fluid and/or blood sample showed skewed X inactivation, it would remain unknown what was occurring throughout the gonads. In fact, X inactivation studies in DSD patients are controversial, as both random and skewed inactivation have been reported (Gunes et al. 2013; Kusz et al. 1999; Vorona et al. 2007). At least one group has argued that it is positional effects rather than X inactivation patterns that determine SRY gene expression on derivative X chromosomes (Sharp et al. 2005). Regardless of the precise molecular mechanism, our case indicates that an SRY+ derivative X chromosome may not necessarily cause a difference of sexual development and that typical female development remains a possibility.
5. Conclusion
We here report detailed cytogenetic analysis of an SRY+ derivative X chromosome in an apparently typical biological female. Importantly, the presence of the SRY gene in a 46,XX fetus does not necessarily result in a difference of sexual development.
Author Contributions
Casey J. Brewer: analysis, writing, editing. Alyxis G. Coyan: analysis, review, editing. Nicki Smith: methodology, review, editing. Brittany Jones: methodology, review, editing. Teresa A. Smolarek: analysis, review, editing. Jie Liu: analysis, writing, review, editing.
Ethics Statement
The Institutional Review Board (IRB) office of Cincinnati Children's Hospital was consulted, and they determined that a full IRB review was not required because this was an anonymized report of a single patient.
Consent
Informed consent could not be obtained because the family was lost to follow‐up. To ensure the privacy of the affected individual and their family, all clinical and personal information has been anonymized.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1. (a) View of the Xq28 terminal region. The Copy Number pipeline detected the Xq terminal deletion, indicated by the red region in the top track. The t(X;Y) was not called by Access software version 1.7. However, two optical maps that match Xq28 have large regions that are unmapped, indicated by the yellow markers (black arrows). (b) View of the Yp arm. Manually selecting the two optical maps from Xq28 reveals that the unmapped regions actually map to Yp (black arrows), indicating the presence of a t(X;Y)(q28;p11.2).
Acknowledgments
The authors would like to thank Cory Lyon and Darlene Strain Swint, librarians at the Edward L. Pratt Research Library, for their valuable assistance. The authors have no conflicts of interest to declare.
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data supporting this study's findings are available in the figures, table, and Supporting Information of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. (a) View of the Xq28 terminal region. The Copy Number pipeline detected the Xq terminal deletion, indicated by the red region in the top track. The t(X;Y) was not called by Access software version 1.7. However, two optical maps that match Xq28 have large regions that are unmapped, indicated by the yellow markers (black arrows). (b) View of the Yp arm. Manually selecting the two optical maps from Xq28 reveals that the unmapped regions actually map to Yp (black arrows), indicating the presence of a t(X;Y)(q28;p11.2).
Data Availability Statement
The data supporting this study's findings are available in the figures, table, and Supporting Information of this article.