Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis

Ezquieta, Begoña; Beneyto, Magdalena; Muñoz-Pacheco, Rafael; Barrio, Raquel; Oyarzábal, M.; Lechuga, J. L.; Luzuriaga, Cristina; F, Hermoso; Quinteiro, Sofía; Martínez, Silvia

doi:10.1002/pd.1584

Cited by 34 publications

(29 citation statements)

References 23 publications

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“…Only patients carrying a severe mutation (about 40% of NC21OHD [compound heterozygous with severe mutations]) and about 10% of hyperandrogenic carriers are at risk. Our group has recently stressed the importance of adequately detecting 21OHD carriers in the partners of NC21OHD patients [24, 32]. …”

Section: Resultsmentioning

confidence: 99%

“…It should be remembered that the adequate segregation of mutations (double microconversions, small conversions including more than one mutation) and a complete characterization of alleles, including the investigation of gene deletions and duplications (i.e. normal alleles carrying gene duplications with the Gln318Stop mutation [24] or PCR amplifiable deletion hybrid genes resulting from a break point upstream of exon 6, including 655G and 8 bp deletion mutations [11]), is required in this type of analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The carrier frequency in siblings used by other authors [16] was not considered adequate for this purpose. The partners of the 21OHD-carriers who had been analyzed for genetic counseling purposes [24] (see table 4, last two columns) were considered a nonbiased general population. As a whole, both severe and mild mutations were more frequent in the hyperandrogenic carriers.…”

Section: Resultsmentioning

confidence: 99%

“…Differential length 5′-extensions of the specific oligonucleotides (table 1) were used. The primer extension protocol used was essentially that previously described [24]. 1 µl of pooled primers (1 pmol of PON1, TNFR2 and IRS1, and 0.1 pmol CAPN and 0.4 pmol IGF2) was used along with 1 µl of the PCR multiplex.…”

Section: Methodsmentioning

confidence: 99%

“…Native acrylamide gels were used to detect the common 8-bp deletion at exon 3, and Southern blotting and semiquantitative primer extension [24] to detect gene deletions and/or duplications, respectively. Complementary direct sequencing (coding regions and intron-exon boundaries) was performed as previously described [25] in nonclassical patients who were not characterized after basic screening, and for whom confirmatory clinical and biochemical information regarding their deficiency was available.…”

Section: Methodsmentioning

confidence: 99%

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Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

et al. 2008

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Aims: Hyperandrogenism, although mostly due to polygenic interactions, is monogenic for some enzymatic adrenal deficiencies. This study evaluates mono- and biallelic 21-hydroxylase deficiency (21OHD)-related hyperandrogenism in pediatric patients. Sensitizing and protective polymorphisms were investigated in carriers and cryptic forms of 21OHD. Methods: The study involved a monogenic analysis of CYP21A2 in patients (375 nonclassical 21OHD [NC21OHD] children; 306 hyperandrogenic 21OHD carriers, n = 306) and a polygenic association study (CAPN10-UCSNP44, PON1-108, TNFR2-M196R, IGF2-ApaI and IRS1-G972R polymorphisms) of 170 hyperandrogenic carriers plus 277 family members (control groups). The metabolic marker 17OH progesterone defined the degree of deficiency; clinical expressivity was determined by pediatric endocrinologists. Results: The group of 21OHD carriers manifesting hyperandrogenism was enriched in the CAPN-UCSNP44 rare variant in homozygosity (4.9 vs. 0.4%, NCBI data for the general population; p = 0.004). In our patients and controls, contrasting distributions were observed for this and another polymorphism, TNFR2-196R. In a recessive model, their rare variants were more frequently detected among the forms with high (p = 0.048) and low (p = 0.034) expressivity respectively. Conclusions: 21OHD-related pediatric hyperandrogenism follows monogenic and polygenic models. The opposite behaviors in terms of clinical expressivity detected for CAPN-UCSNP44 and TNFR2-M196R rare variants suggest these variants to be sensitizing and protective factors respectively in adrenal hyperandrogenism.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

et al. 2008

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Long‐Read Sequencing Identifying the Genetic Complexity of Congenital Adrenal Hyperplasia in the Pedigree

Chen,

Zhao,

et al. 2024

Molec Gen & Gen Med

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BackgroundHigh sequence homology between CYP21A2 and CYP21A1P poses challenges to genetic diagnosis of congenital adrenal hyperplasia (CAH) due to 21‐hydroxylase deficiency (21‐OHD). Traditional genetic testing is unable to provide an accurate diagnosis due to the genetic complexity of CAH.MethodsDeletions, duplications, and recombination breakpoints were precisely identified by long‐read sequencing (LRS).ResultsThis study presented a pregnant woman, a 21‐OHD carrier detected by MLPA, and her husband, a normal subject also detected by MLPA. The fetus was suspected of having 21‐OHD based on clinical presentations such as enlarged adrenal glands, atypical external genitalia and karyotyping of 46, XX. LRS further identified the fetus as having the most severe salt‐wasting (SW) form of 21‐OHD with a compound heterozygote genotype. One allele was TNXA/TNXB CH‐2, while the other allele was CYP21A1P/CYP21A2 CH‐8. LRS precisely determined the genotypes of the fetus's father and grandmother with duplications, which misdiagnosed by MLPA. The multidisciplinary team recommended immediate glucocorticoid and mineralocorticoid treatment for the child after birth to prevent life‐threatening adrenal crisis.ConclusionsLRS provides precise diagnosis for family members with CYP21A2 deletion or duplication, improving disease management and preventing potential adrenal crises. When used in pre‐pregnancy genetic testing, LRS can indicate high genetic risk and guide the appropriate therapy during pregnancy and immediately after birth.

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Carrier detection and prenatal diagnosis of congenital adrenal hyperplasia must identify ‘apparently mild’ CYP21A2 alleles which associate neonatal salt‐wasting disease

et al. 2010

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Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis

Abstract: The proposed method discriminated between the severe Q318X mutation and the normal Q318X variant in gene duplication, and could be a useful complementary tool in prenatal diagnosis and carrier detection.

Cited by 34 publications

References 23 publications

Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

Monogenic and Polygenic Models Detected in Steroid 21-Hydroxylase Deficiency-Related Paediatric Hyperandrogenism

Long‐Read Sequencing Identifying the Genetic Complexity of Congenital Adrenal Hyperplasia in the Pedigree

Carrier detection and prenatal diagnosis of congenital adrenal hyperplasia must identify ‘apparently mild’ CYP21A2 alleles which associate neonatal salt‐wasting disease

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