Expanding the Phenotype of Copy Number Variations Involving NR0B1 (DAX1)

Endocrinology Pediatrics Obstetrics and Gynecology Medicine Cell Biology Biochemistry Genetics Life Sciences
Copy number variations Gonadal dysgenesis NR0B1 gene DAX1 46,XY disorders of sex development Chromosomal microarray analysis Prenatal screening

This study aims to explore the relationship between copy number variations (CNVs) involving the NR0B1 (DAX1) gene and 46,XY gonadal dysgenesis. 46,XY gonadal dysgenesis (GD) is a disorder of sex development caused by the failure of gonads to fully differentiate into testes. This condition can lead to individuals presenting with female or ambiguous external genitalia. Previously, this disease was thought to be associated with duplications of the Nr0b1 gene in the Xp21.2 region of the X chromosome. However, a recent study on complex structural variations suggests that the disease can occur even without direct involvement of the Nr0b1 gene. This indicates that the mechanism by which CNVs in the Xp21.2 region cause 46,XY gonadal dysgenesis is not yet fully understood.

Paper Source

This paper was jointly written by Nathalie Veyt, Griet Van Buggenhout, Koen Devriendt, Kris Van Den Bogaert, and Nathalie Brison, affiliated with the Center for Human Genetics at University Hospitals Leuven-KU Leuven in Belgium. It was published online in the European Journal of Human Genetics on January 10, 2024.

Research Details

Workflow

This study conducted CNV detection on cases from three families, performing genetic and molecular biological analyses. The specific process is as follows: - Family A: Genetic testing was performed on a pair of monochorionic diamniotic (MCDA) female twins during pregnancy. One fetus was diagnosed with a 1.1Mb Xp21.2 duplication, including the Nr0b1 gene. This duplication originated from the father, who had fertility issues. - Family B: Non-invasive prenatal screening (NIPS) detected an Nr0b1 duplication in a mother during pregnancy with a male fetus. Chromosomal analysis confirmed a 712kb Xp21.2 duplication inherited from the mother, ultimately resulting in the birth of a healthy male infant. - Family C: NIPS during the first pregnancy revealed a 468kb Xp21.2 duplication in a 28-year-old woman. Chromosomal microarray analysis confirmed the duplication was of maternal origin. A subsequent IVF-PGT pregnancy avoided transmission of the duplication, resulting in a healthy male infant.

Experimental analysis combined microarray analysis, genetic testing, and non-invasive prenatal screening (NIPS) to provide accurate gene copy number variations. Equipment used included Illumina HiSeq4000 or NovaSeq systems, with data analysis performed using customized bioinformatics methods.

Main Results

The study results show: 1. The 38-year-old father in Family A carries the Nr0b1 duplication, which is the source of his fertility issues. 2. The mother in Family B also carries the Nr0b1 duplication, as do her two healthy sons. 3. The mother in Family C carries the Nr0b1 duplication, which is a de novo mutation.

In all three families, the affected children were healthy boys carrying the Nr0b1 gene duplication, without significant symptoms of gonadal dysgenesis. Unlike all previously reported cases involving female or ambiguous external genitalia, this is the first report of Nr0b1 duplication in phenotypically normal males.

Conclusions and Significance

This study broadens the phenotypic spectrum associated with Nr0b1 gene copy number variations, providing important reference for clinicians in prenatal counseling and decision-making. Previously, all Xp21.2 CNVs were associated with 46,XY gonadal dysgenesis. Through this study, we have for the first time determined that Nr0b1 duplications can also exist in normal males, possibly only manifesting as potential fertility issues. This provides a reference for screening and genetic counseling, and especially highlights the necessity of finding these duplications in healthy women in prenatal screening contexts.

Research Highlights

  • First Report: First report of Nr0b1 gene duplication in three phenotypically normal males.
  • Broadened Phenotypic Spectrum: Expands the phenotypic spectrum associated with Nr0b1, challenging previous observations only in cases of sex development disorders.
  • Important Clinical Value: Has significant implications for counseling and decision-making, especially in prenatal contexts.

Suggestions for Further Research

Future research could focus on exploring the regulatory mechanisms of Nr0b1 gene expression and its specific effects on gonadal development. Additionally, long-term follow-up on fertility issues in males carrying Nr0b1 duplications could further assess their potential impact on fertility.

Significance and Value

This study greatly advances our understanding of the association between the NR0B1 gene and 46,XY gonadal dysgenesis, providing a new perspective on this gene variation in healthy backgrounds, and offering practical guidance for clinical practice. Such research not only helps understand gene function and expression regulation but also provides important basis for genetic screening and counseling.