Clinical Report: Revealing Pseudo-Homozygosity in CYP21A2 Through Intergenerational Gene Conversion Expansion

Overview

This case study highlights the complexities of genetic testing in Congenital Adrenal Hyperplasia (CAH) due to CYP21A2 mutations, particularly the phenomenon of pseudo-homozygosity.

Background

Congenital Adrenal Hyperplasia (CAH) is primarily caused by mutations in the CYP21A2 gene, leading to significant clinical implications. The genetic complexity of this locus, including the potential for pseudo-homozygosity, poses challenges for accurate diagnosis and management.

Data Highlights

No numerical data or trial data available in the source material.

Key Findings

• The study describes a case of pseudo-homozygosity in a child with CAH due to intergenerational gene conversion in the CYP21A2 gene.
• Initial genetic screening indicated homozygosity for the p.Ile173Asn variant, which was misleading due to allele dropout.
• Comprehensive testing revealed a heterozygous gene conversion in the mother, leading to a misinterpretation of the child's genotype.
• The father's suspected deletion was excluded based on probe-binding interference from his heterozygous mutation.
• Successful prenatal management was achieved through early identification of the wild-type female fetus via Chorionic Villus Sampling.

Clinical Implications

Clinicians should be aware of the potential for pseudo-homozygosity and consider advanced genetic techniques for accurate assessment.

Conclusion

This case illustrates the complexities involved in managing CAH, particularly in familial cases.

Related Resources & Content

1. The Journal of Clinical Endocrinology & Metabolism, 2023 -- Utilizing Long-Read Sequencing to Unravel the Complex Structure of CYP21A2 in a Large Cohort of Patients with 21-Hydroxylase Deficiency
2. the pathologist, 2017 -- The Power of Pedigree
3. The Journal of Clinical Endocrinology & Metabolism, 2023 -- Phenotypic Associations with SOX9 Upstream Duplications: Advancements in Understanding Clinical Presentation and Diagnosis
4. The Journal of Clinical Endocrinology & Metabolism, 2023 -- Chimeric CYP21A1P/CYP21A2 Genes in 21-Hydroxylase Deficiency Detected by Long-Read Sequencing and Phenotypes Correlation
5. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline, 2018
6. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency, 2020
7. Frontiers, 2026 -- Unmasking Pseudo-Homozygosity in CYP21A2: Intergenerational Gene Conversion Expansion and the Necessity of Multimodal Genetic Testing
8. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society* Clinical Practice Guideline | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic
9. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency - PMC
10. Frontiers | Unmasking Pseudo-Homozygosity in CYP21A2: Intergenerational Gene Conversion Expansion and the Necessity of Multimodal Genetic Testing