NR3C2 microdeletions—an underrecognized cause of pseudohypoaldosteronism type 1A: a case report and literature review
Abstract Objectives Pseudohypoaldosteronism type 1A (PHA1A) is caused by haploinsufficiency of the mineralocorticoid receptor (MR). Heterozygous small insertions/deletions, transitions, and/or transversions within NR3C2 comprise the majority (85%-90%) of pathogenic copy number variants. Structural c...
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Published in | Laboratory medicine Vol. 55; no. 5; pp. 640 - 644 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
US
Oxford University Press
04.09.2024
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Subjects | |
Online Access | Get full text |
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Summary: | Abstract
Objectives
Pseudohypoaldosteronism type 1A (PHA1A) is caused by haploinsufficiency of the mineralocorticoid receptor (MR). Heterozygous small insertions/deletions, transitions, and/or transversions within NR3C2 comprise the majority (85%-90%) of pathogenic copy number variants. Structural chromosomal abnormalities, contiguous gene deletion syndromes, and microdeletions are infrequent. We describe a neonate with PHA1A due to a novel NR3C2 microdeletion involving exons 1-2.
Methods
Literature review identified 39 individuals with PHA1A due to NR3C2 microdeletions. Transmission modality, variant description(s), testing method(s), exon(s) deleted, and affected functional domain(s) were characterized.
Results
In total, 40 individuals with NR3C2 microdeletions were described: 19 involved contiguous exons encoding a single MR domain; 21 involved contiguous exons encoding multiple MR domains. Transmission modality frequency was familial (65%), de novo (20%), or unknown (15%). Sequencing (Sanger or short-read next-generation) failed to detect microdeletions in 100% of tested individuals (n = 38). All were detected using deletion/duplication testing modalities. In 2 individuals, only microarray-based testing was performed; microdeletions were detected in both cases.
Conclusion
Initial testing for PHA1A should rely on sequencing to detect the most common genetic alterations. Deletion/duplication analysis should be performed when initial testing is nondiagnostic. Most NR3C2 microdeletions are parentally transmitted, thus highlighting the importance of familial genetic testing and counseling. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Review-5 content type line 23 ObjectType-Case Study-4 ObjectType-Feature-2 ObjectType-Report-3 |
ISSN: | 0007-5027 1943-7730 1943-7730 |
DOI: | 10.1093/labmed/lmae005 |