Novel Gene Variants in SRY-negative 46, XX male syndrome with Bone Marrow Failure by Whole Exome Sequencing
Ao‐Li ZhangLi Xian ChangLi ZhangChao LiuLi Peng LiuXiaohong ChenMeihui YiYang LanLuyang ZhangYu Li Caijing fengWenqi WuYingchi ZhangXiaofan Zhu
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46, XX male syndrome is a rare disorder of sex development. One-tenth of 46, XX male syndrome is sex-determining region Y (SRY)-negative. We used whole-exome sequencing (WES) analysis associated genes to investigate the underlying genetic etiology of 46, XX male syndrome patients with bone marrow failure with a typical male phenotype. WES reveals SRY and SRY-box family genes were negative. Simultaneously, gene variants were detected in female pathway, testis development, and steroid receptor genes. There are undefined gene variants associated with congenital bone marrow failure. WES proved an efficient diagnostic method toward 46, XX male syndrome patients with hematological disorder.Keywords:
Testis determining factor
Prenatal diagnosis of disorder of sex development (DSD) is very rare and is estimated to occur in 1∕2500 pregnancies. A group of DSDs are the 46,XX testicular DSD. Today, the incidence of 46,XX testicular DSD is estimated at 1∕20 000 newborn males. A majority of males with DSD have an unbalanced X;Y exchange involving the pseudoautosomal region, with translocation of the sex-determining region of the Y (SRY) gene onto Xp23.3. We present a rare case of very early prenatal diagnosis and management of a fetus with SRY-positive 46,XX testicular DSD.
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Disorders of human sex determination result in malformations of the external and internal genitalia. These malformations may vary from sexual ambiguity to complete sex reversal (XY female, XX male). Most of the knowledge of the molecular mechanisms involved in the mammalian sex determination pathway has been derived from the genetic analysis of intersex patients. Clinical management of these conditions critically depends on a precise understanding of their pathophysiology. Until recently, only transcription factors such as SRY, SOX9, DAX1, WT1 and SF1 were known to be responsible for abnormal gonadal development and sexual ambiguity. Gonadal dysgenesis may be isolated, as in the case of SRY mutations, or associated with abnormal development of other organs, such as bone or adrenals, consistent with the spatial expression profile of the disrupted genes (SOX9 or SF1). WNT4 is a new sex-determining signalling molecule. Deletions of Wnt4 were shown to be responsible for the masculinization of XX mouse pups while its duplication and overexpression in humans leads to XY sex reversal. Similarly, duplications of loci containing DAX1 or SOX9 have also been shown to cause sex reversal. These results support the emerging concept that mammalian sex determination is dosage sensitive at multiple steps of its pathway.
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In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and internal genitalia. Variants in transcription factors such as SRY, NR5A1 and SOX9, can cause changes in gonadal development often associated with ambiguity of the external genitalia.This study has been conducted to determine the frequency, types and associated genetic alterations in patients with DSD in the Algerian population.Thirty patients were included. Based on their clinical presentation, thirteen patients presented with ambiguous external genitalia, thirteen patients presented with hypospadias and four patients presented with bilateral undescended testes. Karyotype analysis was performed on peripheral blood lymphocytes using standard R-banding. DNA was isolated from blood leukocytes for PCR reaction and mutational analysis of SRY and NR5A1 was done by direct sequencing.Most patients with ambiguous genitalia had a 46,XY karyotype. One patient had a deletion of SRY, otherwise no point mutations in SRY or NR5A1 genes were identified. However, a single NR5A1 polymorphism (p.Gly146Ala) in patient with 46,XX DSD has been detected.The absence of mutations in these genes suggests that there are others genes playing an important role in sex development and differentiation.
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Abstract Differentiation of the bipotential gonad into testis is initiated by the Y chromosome‐linked gene SRY (Sex‐determining Region Y) through upregulation of its autosomal direct target gene SOX9 ( Sry ‐related HMG box‐containing gene 9). Sequence and chromosome homology studies have shown that SRY most probably evolved from SOX3 , which in humans is located at Xq27.1. Mutations causing SOX3 loss‐of‐function do not affect the sex determination in mice or humans. However, transgenic mouse studies have shown that ectopic expression of Sox3 in the bipotential gonad results in upregulation of Sox9 , resulting in testicular induction and XX male sex reversal. However, the mechanism by which these rearrangements cause sex reversal and the frequency with which they are associated with disorders of sex development remains unclear. Rearrangements of the SOX3 locus were identified recently in three cases of human XX male sex reversal. We report on a case of XX male sex reversal associated with a novel de novo duplication of the SOX3 gene. These data provide additional evidence that SOX3 gain‐of‐function in the XX bipotential gonad causes XX male sex reversal and further support the hypothesis that SOX3 is the evolutionary antecedent of SRY . © 2012 Wiley Periodicals, Inc.
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The genetics of sex determination is a child of the twentieth century, which overturned the previously held view that sex was determined by the environment. The last quarter of the century witnessed an active search for sex-determining genes in mammals. Although successful, the modus operandi of these genes remained unknown, and the relationship between the sex-determining systems of mammals and other vertebrates remained enigmatic. To overcome these problems, scientists in the 21st century should heed William Bateson's counsel to treasure exceptions, for they point the way to progress. One exception to conventional concepts of sex determination is the bilaterally asymmetrical distribution of ovaries and testes in true hermaphroditism. Ovaries favour the left side in humans and the right side in mice. Observations suggesting that a reversal of asymmetry may occur with increasing organ size may point to a possible explanation. A reevaluation is also required regarding the beginning of sex differentiation, in view of mounting evidence of a sex difference in growth rates of early embryos. Another question to be settled is whether the function of SRY is confined to the fetal gonad. The recent demonstration that Sry induces cell proliferation in the fetal mouse gonad (Schmahl et al., 2000) further emphasizes the importance of differential growth in sex determination and differentiation. It is suggested that SRY represents an additional growth-promoting gene sequestered by mammals to enable the XY embryo to undergo male sex differentiation in the female hormonal environment of the uterus. An increased awareness of the relationship between growth and gonadal differentiation should lead to a better understanding of sex determination in mammals and an ability to relate the function of sex-determining genes to the effects of environmental factors. J. Exp. Zool. 290:484-489, 2001.
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Objectives Disorders of sex development(DSD)can result in discordance between the chromosomal and anatomicand/orphenotypic sex of a patient. Reporting patients with uncommon karyotypes associated with DSD is important for clinical comparison of developmental outcomes, and management. Methods We describe three female patients with karyotypes resulting in DSD and the use of a combination of chromosomes and FISH techniques to identify potential causes. Results The first patient was mosaic for idic(Y) that was negative for SRY by FISH. The second patient had idic(Y) that was positive for SRY by FISH. The third patient had an unbalanced translocation between the X chromosome and chromosome 2 [der(2)(X;2)] and XY. These three patients illustrate three different genetic mechanisms underlying DSD. Conclusion Our findings expand the list of abnormal karyotypes that can be associated with DSD and highlight the importance of SRY and DAX1 in phenotypic and functional sexual development.
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Normal sex development depends on the precise spatio-temporal sequence and coordination of mutually antagonistic activating and repressing factors. These factors regulate the commitment of the unipotential gonad into the binary pathways governing normal sex development. Typically, the presence of the SRY gene on the Y chromosome triggers the cascade of molecular events that lead to male sex development. Disorders of sex development comprise a heterogeneous group of congenital conditions associated with atypical development of internal and external genitalia. These disorders are generally attributed to deviations from the typical progression of sex development. Disorders of sex development can be classified into several categories including chromosomal, gonadal, and anatomic abnormalities. Genetic tools such as microarray analyses and next-generation sequencing techniques have identified novel genetic variants among patients with disorders of sexual development. Most importantly, patient management needs to be individualized, especially for decisions related to sex of rearing, surgical interventions, hormone treatment, and potential for fertility preservation.
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SRY related high mobility group box (Sox) transcription factors have emerged in the animal kingdom to help cells maintain stemness, commit to a specific lineage, proliferate or die. Encoded by 20 genes in humans and mice they show a highly conserved high-mobility group boxdomain, which was originally identified in SRY, the sex determining region on the Y chromosome. This has derived from a high mobility group domain characterized of chromatin associated proteins. HMG (high mobility group) non histone chromosomal proteins include the AT hook, HMGN, and HMG domain families.
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The commitment of the embryonic gonad towards the male or female fate is a sequential and complex developmental process. The sex-independent growth and development of the adrenogonadal primordium into the bipotential gonadal ridge is committed to the formation of testis in the presence of the SRY gene on the Y chromosome. SRY upregulates the expression of SOX9 that sets into motion a cascade of complex genetic interactions for the formation of male internal and external genitalia whilst repressing the formation of female genitalia. The initiation and maintenance of somatic sex of the gonad as either male or female is achieved by suppression of the alternate fate. However, at least in mice, the primary sex-determining decision is not final but is maintained in adulthood by a mutually antagonistic double-repressive pathway. In the human, any imbalance between these two antagonistic genetic and physiological pathways results in inappropriate gonad differentiation and function leading to disorders of sex development (DSD). Genetic analysis of individuals presenting with DSD and sex-reversed mice has revealed a number of sexually dimorphic genes that are involved in the formation of mammalian gonads, which are discussed in this chapter. Despite an increase in the knowledge of genes involved in mammalian sex determination, the molecular mechanisms remain by and large undetermined. The use of novel 'omics' technologies for analyzing a large number of patients with DSD, and careful assessment of the resulting datasets may result in the identification of novel genetic factors in human sex determination and lead to the development of novel ex vivo cellular models.
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