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

Ezquieta, Begoña; Santomé, Luis; Barrio, Raquel; López-Siguero, Juan Pedro; Oliver, Antonio; Ramírez, Joaquín; Rodríguez, I. Marcelino; Muñoz-Pacheco, Rafael

doi:10.1002/pd.2537

Cited by 11 publications

(3 citation statements)

References 27 publications

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“…An efficient multistep approach ( 64 ) allows a comprehensive mutation analysis. Apparently mild alleles which are not really such are those carrying the variant c.92C>T [p.Pro31Leu] with a cis pseudogene-conversion in 5’ ( 26 , 56 , 66 , 67 ), and those carrying the variant c.844G>T [p.Val282Leu] in cis with the intronic change c.292+5G>A, an alteration observed in SW from Mediterranean populations ( 15 , 68 ) ( Figure 1 and Supplementary Table 1 ).…”

Section: Cyp21a2 Genotypingmentioning

confidence: 99%

“…The high carrier frequency of severe variants in general population (about 1:60) ( 15 , 96 , 97 ) ( Supplementary Table 1 , false severe alleles) makes reasonable to refine the risk of having an affected child by genotyping CYP21A2 in couples where one member is affected/carrier. Individuals with CLF present a risk of 1:120 of having a newborn affected with a CLF.…”

Section: Contribution Of Cyp21a2 Genotypingmentioning

confidence: 99%

“…It is still accomplished on samples from corionic villus through direct analysis addressed to investigate those alterations detected in the index case. An additional indirect analysis ( 6 , 15 , 74 ) provides the possibility of detecting maternal contamination and avoids eventual allele dropout artefacts.…”

Section: Contribution Of Cyp21a2 Genotypingmentioning

confidence: 99%

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Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency: A Practical Approach

Arriba

Ezquieta

2022

Front. Endocrinol.

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Adrenal insufficiency in paediatric patients is mostly due to congenital adrenal hyperplasia (CAH), a severe monogenic disease caused by steroid 21-hydroxylase deficiency (21-OHD, encoded by the CYP21A2 gene) in 95% of cases. CYP21A2 genotyping requires careful analyses that guaranty gene-specific PCR, accurate definition of pseudogene-gene chimeras, gene duplications and allele dropout avoidance. A small panel of well-established disease-causing alterations enables a high diagnostic yield in confirming/discarding the disorder not only in symptomatic patients but also in those asymptomatic with borderline/positive results of 17-hydroxyprogesterone. Unfortunately, the complexity of this locus makes it today reluctant to high throughput techniques of massive sequencing. The strong relationship existing between the molecular alterations and the degree of enzymatic deficiency has allowed genetic studies to demonstrate its usefulness in predicting/classifying the clinical form of the disease. Other aspects of interest regarding molecular studies include its independence of physiological variations and analytical interferences, its usefulness in the diagnosis of simple virilizing forms in males and its inherent contribution to the genetic counseling, an aspect of great importance taking into account the high carrier frequency of CAH in the general population. Genetic testing of CYP21A2 constitutes an irreplaceable tool to detect severe alleles not just in family members of classical forms but also in mild late-onset forms of the disease and couples. It is also helpful in areas such as assisted reproduction and preimplantation diagnosis. Molecular diagnosis of 21-OHD under expert knowledge definitely contributes to a better management of the disease in every step of the clinical course.

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