ArticleJournal of endocrinological investigation2026
Functional analysis of 11 CYP21A2 variants reveals greater loss of enzyme activity in cis variants and improves genotype-phenotype correlation in 21-hydroxylase deficiency.
Article in Journal of endocrinological investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors.
Funding
Abstract
purposeClinical severity of 21-hydroxylase deficiency (21-OHD) is primarily determined by the CYP21A2 genotype and residual enzymatic activity of mutant CYP21A2. However, CYP21A2 variants often lack functional characterization, and the pathogenic contribution of multiple variants arranged in cis remains poorly understood. We aimed to determine the residual 21-hydroxylase activity of 11 rare CYP21A2 variants, assess the combined functional impact of cis-configured double variants, and refine genotype-phenotype correlations.
methodsAmong 713 patients with 21-OHD, 14 carried rare CYP21A2 variants. Targeted long-read sequencing was used to resolve allele structures and phase variants. Pathogenicity was evaluated using conservation analysis, in silico prediction, enzyme activity assays, and minigene-based splicing analysis. Clinical data were reviewed to examine genotype-phenotype correlations.
resultsWe identified 11 CYP21A2 variants in 14 patients, including 10 missense variants and one deep intronic variant (c.738 + 75 C > T); four were novel (p.Ile173Phe, p.Gly179Glu, p.Asp259Val, p.Pro361Leu). Two cis-configured double-variant alleles were confirmed: p.[His63Leu; Val70Leu] and p.[Thr124Ile; Ile173Asn]. Functional assays showed that all 10 missense variants exhibited reduced activity across both substrate conversions. Both cis-configured double-variant alleles showed greater functional impairment than their corresponding single variants, a pattern consistent with a cumulative functional effect. The intronic variant c.738 + 75C > T caused partial intron 6 retention (73-bp insertion), with a predicted frameshift and likely nonsense-mediated decay. Overall concordance between genotype and phenotype was 71.4%.
conclusionThese findings expand the functional spectrum of CYP21A2 variants in 21-OHD and support clinical interpretation of rare alleles. Integration of long-read phasing with enzyme and splicing assays improves allele-level pathogenicity assessment, clarifies the greater functional impairment associated with cis-configured double-variant alleles, and enhances risk stratification and counseling.
Indexed as
Identifiers
42606814What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.