Isolated 46,XY Gonadal Dysgenesis in Two Sisters Caused by a Xp21.2 Interstitial Duplication Containing the DAX1 Gene

• Published in: The journal of clinical endocrinology and metabolism Vol. 92; no. 8; pp. 3305 - 3313
• Main Authors: Barbaro, Michela, Oscarson, Mikael, Schoumans, Jacqueline, Staaf, Johan, Ivarsson, Sten A., Wedell, Anna
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.08.2007; Endocrine Society
• Subjects: Adolescent; Adult; Artificial chromosomes; Bacterial artificial chromosomes; Biological and medical sciences; Cancer and Oncology; Cancer och onkologi; Chromosomes, Human, Pair 21 - genetics; Clinical Medicine; Computational Biology; Copy number; DAX-1 Orphan Nuclear Receptor; DAX1 gene; DNA - analysis; DNA - genetics; DNA-Binding Proteins - genetics; Dosage; Endocrinopathies; Feeding. Feeding behavior; Female; Fluorescence in situ hybridization; Fundamental and applied biological sciences. Psychology; Gene Amplification; Gene Dosage; Gene Duplication; Gene rearrangement; Genes; Gonadal dysgenesis; Gonadal Dysgenesis, 46,XY - genetics; Homologous recombination; Humans; In Situ Hybridization, Fluorescence; Intellectual disabilities; Karyotypes; Klinisk medicin; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Pediatrics; Pediatrik; Phenotype; Phenotypes; Phenotypic variations; Receptors, Retinoic Acid - genetics; Repressor Proteins - genetics; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity analysis; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Human; Obesity; Duplication; Nutrition; Nutrition disorder; Metabolic diseases; Sexual differentiation disorder; In vitro; Genital diseases; Dysgenesia gonad; Gene; Malformation; Genetics; Interstitial; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2007-0505

Context: Testis development is a tightly regulated process that requires an efficient and coordinated spatiotemporal action of many factors, and it has been shown that several genes involved in gonadal development exert a dosage effect. Chromosomal imbalances have been reported in several patients presenting with gonadal dysgenesis as part of severe dysmorphic phenotypes. Results: We screened for submicroscopic DNA copy number variations in two sisters with an apparent normal 46,XY karyotype and female external genitalia due to gonadal dysgenesis, and in which mutations in known candidate genes had been excluded. By high-resolution tiling bacterial artificial chromosome array comparative genome hybridization, a submicroscopic duplication at Xp21.2 containing DAX1 (NR0B1) was identified. Using fluorescence in situ hybridization, multiple ligation probe amplification, and PCR, the rearrangement was further characterized. This revealed a 637-kb tandem duplication that in addition to DAX1 includes the four MAGEB genes, the hypothetical gene CXorf21, GK, and part of the MAP3K7IP3 gene. Sequencing and analysis of the breakpoint boundaries and duplication junction suggest that the duplication originated through a coupled homologous and nonhomologous recombination process. Conclusions: This represents the first duplication on Xp21.2 identified in patients with isolated gonadal dysgenesis because all previously described XY subjects with Xp21 duplications presented with gonadal dysgenesis as part of a more complex phenotype, including mental retardation and/or malformations. Thus, our data support DAX1 as a dosage sensitive gene responsible for gonadal dysgenesis and highlight the importance of considering DAX1 locus duplications in the evaluation of all cases of 46,XY gonadal dysgenesis.