Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene

Concolino, Paola; Costella, Alessandra

doi:10.1007/s40291-018-0319-y

Cited by 82 publications

(71 citation statements)

References 80 publications

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“…Additionally, 3 children belonging to the SV group exhibited GnRH independent precocious puberty. At this time, more than 200 mutations in the CYP21A2 gene have been reported in numerous studies and there is a good concordance between the clinical phenotype and the patient genotypic findings [13,16,17,21,[37][38][39][40]. The genetic population profile of CAH and endocrinopathies in the Cypriot population is characterized by low consanguinity rates and by similarities to what is observed regarding these disorders in the Eastern Mediterranean countries [41,42].…”

Section: Discussionmentioning

confidence: 65%

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The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

et al. 2019

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Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. The study refers to CAH patients of Greek-Cypriot ancestry between years 2007 and 2018. One hundred and twenty patients with various degrees of CAH were categorized and genotyped. The patients were categorized in 4 mutation groups based on their clinical and biochemical findings. The majority of patients (85.0%) belonged to the non-classic (NC)-CAH form and the disorder was more often diagnosed in females (71.7%). The most severe classic salt-wasting (SW) form was identified in 11 neonates (9.2%). Seven (5.8%) children were also identified with the simple virilizing (SV) form and a median presentation age of 5 years [interquartile range (IQR) 3.2–6.5]. In the 240 nonrelated alleles, the most frequent mutation was p.Val281Leu (60.0%) followed by c.655 A/C>G (IVS2–13A/C>G) (8.8%), p.Pro453Ser (5.8%), DelEx1–3 (4.6%), p.Val304Met (4.6%), and p.Gln318stop (4.2%). Other less frequent mutations including rare deletions were also identified. Following our recent report that the true carrier frequency of CYP21A2 in Greek-Cypriots is 1:10, this study reports that the CAH prevalence is predicted around 1.7 cases per 10 000 people. Therefore, the up-to-date 120 CAH patients identified by our group make only the 6.9% of the ones estimated (approximately 1750) to exist in the Greek Cypriot population. The compiled data from a coherent population such as the Greek-Cypriot could be valuable for the antenatal diagnosis, management and genetic counselling of the existing and prospect families with CAH.

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Section: Discussionmentioning

confidence: 65%

“…A number of studies demonstrated strong association between genotype and phenotype and over the most recent years mutation detection rate led to the identification of a large number of CYP21A2 defects [12,13]. Since 2007 our group has extensively studied the genetic implication of CYP21A2 in Cypriot patients with CAH.…”

Section: Introductionmentioning

confidence: 99%

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

et al. 2019

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“…While nonspecific mappings due to high homology regions can be largely remedied by the use of longer reads in many instances, this does not necessarily mean these regions are free from issues. CYP21A2 is the gene for 21-hydroxylase deficiency which is the most common cause of congenital adrenal hyperplasia (CAH) 38 . CAH is included in NBS since it can be life-threatening within a few days of birth in its severest clinical forms.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing of newborn screening genes: the accuracy of short-read mapping

et al. 2020

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Newborn screening programs are an integral part of public health systems aiming to save lives and improve the quality of life for infants with treatable disorders. Technological advancements have driven the expansion of newborn screening programs in the last two decades and the development of fast, accurate next-generation sequencing technology has opened the door to a range of possibilities in the field. However, technological challenges with short-read next-generation sequencing technologies remain significant in highly homologous genomic regions such as pseudogenes or paralogous genes and need to be considered when implemented in screening programs. Here, we simulate 50 genomes from populations around the world to test the extent to which high homology regions affect short-read mapping of genes related to newborn screening disorders and the impact of differential read lengths and ethnic backgrounds. We examine a 158 gene screening panel directly relevant to newborn screening and identify gene regions where read mapping is affected by homologous genomic regions at different read lengths. We also determine that the patient's ethnic background does not have a widespread impact on mapping accuracy or coverage. Additionally, we identify newborn screening genes where alternative forms of sequencing or variant calling pipelines should be considered and demonstrate that alterations to standard variant calling can retrieve some formerly uncalled variants.

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“…The most frequent variants impairing 21-OH function are the result of recombination and/or gene conversion events between the functional CYP21A2 gene and its functionally inactive (rendered inactive by variants impairing 21-OH function) pseudogene CYP21A1P [ 1 , 2 , 65 – 67 ]. In a recent review Concolino et al [ 68 ] listed more than 200 CAH causing variants of the CYP21A2 gene. These include the following most common variants affecting 21-OH function representing about 70–75% of CAH alleles listed in Table 4 .…”

Section: -Oh Genotypingmentioning

confidence: 99%

EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency

2020

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Molecular genetic testing for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is offered worldwide and is of importance for differential diagnosis, carrier detection and adequate genetic counseling, particularly for family planning. In 2008 the European Molecular Genetics Quality Network (EMQN) for the first time offered a European-wide external quality assessment scheme for CAH (due to 21-OH deficiency). The interest was great and over the last years at about 60 laboratories from Europe, USA and Australia regularly participated in that scheme. These best practice guidelines were drafted on the basis of the extensive knowledge and experience got from those annually organized CAH-schemes. In order to obtain the widest possible consultation with practicing laboratories the draft was therefore circulated twice by EMQN to all laboratories participating in the EQA-scheme for CAH genotyping and was updated by that input. The present guidelines address quality requirements for diagnostic molecular genetic laboratories, as well as criteria for CYP21A2 genotyping (including carrier-testing and prenatal diagnosis). A key aspect of that article is the use of appropriate methodologies (e.g., sequencing methods, MLPA (multiplex ligation dependent probe amplification), mutation specific assays) and respective limitations and analytical accuracy. Moreover, these guidelines focus on classification of variants, and the interpretation and standardization of the reporting of CYP21A2 genotyping results. In addition, the article provides a comprehensive list of common as well as so far unreported CYP21A2-variants.

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Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene

Cited by 82 publications

References 80 publications

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

Next-generation sequencing of newborn screening genes: the accuracy of short-read mapping

EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency

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