Unbalanced Y;7 Translocation between Two Low-Similarity Sequences Leading to SRY-Positive 45,X Testicular Disorders of Sex Development

Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.

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Genomic Basis of Aromatase Excess Syndrome: Recombination- and Replication-Mediated Rearrangements Leading to CYP19A1 Overexpression

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2520 ◽

2013 ◽

Vol 98 (12) ◽

pp. E2013-E2021 ◽

Cited By ~ 14

Author(s):

Maki Fukami ◽

Takayoshi Tsuchiya ◽

Heike Vollbach ◽

Kristy A. Brown ◽

Shuji Abe ◽

...

Keyword(s):

Gc Content ◽

Replication Timing ◽

Nonhomologous End Joining ◽

Coding Region ◽

End Joining ◽

Clinical Consequences ◽

Underlying Mechanisms ◽

Nonallelic Homologous Recombination ◽

Genomic Disorders ◽

Flanking Regions

Context: Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated. Objective: The aim of the study was to clarify such unsolved matters. Design, Setting, and Methods: We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions. Results: Novel rearrangements included simple duplication involving exons 1–10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 and the property of the fused promoters. Sequences at the fusion junctions suggested nonallelic homologous recombination, nonhomologous end-joining, and replication-based errors as the underlying mechanisms. The breakpoint-flanking regions were not enriched with GC content, palindromes, noncanonical DNA structures, or known rearrangement-associated motifs. The rearrangements resided in early-replicating segments. Conclusions: These results indicate that AEXS is caused by duplications involving CYP19A1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes. Our data support the notion that phenotypes depend on the dosage of CYP19A1 and the characteristics of the fused promoters. Furthermore, we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms, independent of the known rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders.

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Prenatal diagnosis of 17-hydroxylase/17,20-lyase deficiency (17OHD) in a case of 46,XY sex discordance and low maternal serum estriol

Case Reports in Perinatal Medicine ◽

10.1515/crpm-2018-0009 ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Lauren Mohnach ◽

Sarah Mazzola ◽

Daniel Shumer ◽

Deborah R. Berman

Keyword(s):

Prenatal Diagnosis ◽

Parental Stress ◽

Disorders Of Sex Development ◽

Rare Condition ◽

Maternal Serum ◽

Diagnostic Challenge ◽

Lyase Deficiency ◽

Sex Development ◽

Seamless Transition ◽

Endocrine Profile

Abstract Background A discrepancy between the fetal karyotype and the appearance of genitalia on ultrasound can be a diagnostic challenge. In these cases, it is difficult to shorten the extensive list of differential diagnoses without information on internal anatomy and endocrine profile. Case presentation Here, we describe a diagnosis of 17-hydroxylase/17,20-lyase deficiency (17OHD), which was suspected based on low maternal serum estriol in the setting of 46,XY genitalia discordance. Through collaboration between maternal-fetal medicine and disorders of sex development (DSD) teams, the patient was counseled about the diagnosis and postnatal management plans were made. Conclusions This case illustrates how prenatal diagnosis of this rare condition led to reduced parental stress and seamless transition to postnatal care.

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