Lack of genotypephenotype correlation in congenital adrenal hyperplasia due to a CYP21A2-like gene

Leccese, Angelica; Longo, Vittoria; Dimatteo, Claudia; Girolamo, Giuseppe De; Trunzo, Roberta; D’Andrea, Giovanna; Bafunno, Valeria; Margaglione, Maurizio; Santacroce, Rosa

doi:10.1016/j.cca.2014.07.009

Cited by 5 publications

(5 citation statements)

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“…For both cases, only the 10 most common variants were analyzed, and the evaluation of duplicated genes by multiplex ligation-dependent probe amplification or Southern-blotting was not conducted. The existence of a trimodular haplotype has been reported in many populations [24, 38, 47, 48]. For instance, a random sample of the Spanish population showed that 7% of the individuals carried at least one chromosome with duplicated CYP21A2 [18].…”

Section: Discussionmentioning

confidence: 99%

CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

et al. 2019

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Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype–phenotype correlation. Methods: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype–phenotype correlation. Results: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients’ stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype–phenotype correlation (80%). Conclusion: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype–phenotype correlation observed.

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Section: Discussionmentioning

confidence: 99%

CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

et al. 2019

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“…Several studies based on the normal steroid levels of subjects with two carried CAH variants have found indirect evidence proving that one of the two CYP21A2 associated with the c.955C4T variant in one chromosome expresses active steroid 21-hydroxylase enzyme. [36][37][38][39] However, direct evidence for the functional CYP21A2 in the middle segment was provided by the current study for the first time. In the adrenal specimen of a patient with NFAI, the CYP21A2 in the middle segment of the LBSASB RCCX structure produced an mRNA transcript differing from the transcripts of the CYP21A2 copies in the 3′-segment and the other chromosome, and this middle segmentspecific CYP21A2 transcript was detected.…”

Section: Discussionmentioning

confidence: 52%

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics

et al. 2017

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There is a difficulty in the molecular diagnosis of congenital adrenal hyperplasia (CAH) due to the c.955C>T (p.(Q319*), formerly Q318X, rs7755898) variant of the CYP21A2 gene. Therefore, a systematic assessment of the genetic and evolutionary relationships between c.955C>T, CYP21A2 haplotypes and the RCCX copy number variation (CNV) structures, which harbor CYP21A2, was performed. In total, 389 unrelated Hungarian individuals with European ancestry (164 healthy subjects, 125 patients with non-functioning adrenal incidentaloma and 100 patients with classical CAH) as well as 34 adrenocortical tumor specimens were studied using a set of experimental and bioinformatic methods. A unique, moderately frequent (2%) haplotypic RCCX CNV structure with three repeated segments, abbreviated to LBSASB, harboring a CYP21A2 with a c.955C>T variant in the 3'-segment, and a second CYP21A2 with a specific c.*12C>T (rs150697472) variant in the middle segment occurred in all c.955C>T carriers with normal steroid levels. The second CYP21A2 was free of CAH-causing mutations and produced mRNA in the adrenal gland, confirming its functionality and ability to rescue the carriers from CAH. Neither LBSASB nor c.*12C>T occurred in classical CAH patients. However, CAH-causing CYP21A2 haplotypes with c.955C>T could be derived from the 3'-segment of LBSASB after the loss of functional CYP21A2 from the middle segment. The c.*12C>T indicated a functional CYP21A2 and could distinguish between non-pathogenic and pathogenic genomic contexts of the c.955C>T variant in the studied European population. Therefore, c.*12C>T may be suitable as a marker to avoid this genetic confound and improve the diagnosis of CAH.

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“…Baumgartner-Parzer et al ( 25 ) reported that the consistency between genotype and clinical phenotype was 80%. However, genotype and clinical phenotype are not always completely consistent, and the same 21-OHD gene mutation in patients with CAH may result in different clinical phenotypes ( 26 , 27 ). New et al ( 28 ) reported that certain mutations, including the P30L, I2Gand I172N mutations, were prone to yield different CAH phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel compound heterozygous mutation of the CYP21A2 gene causing 21‑hydroxylase deficiency in a Chinese pedigree

Liu

Zhang

et al. 2018

Mol Med Report

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21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia. Inherited in an autosomal recessive manner, 21-OHD is caused by mutations in the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene. The present study was designed to investigate the genetic characteristics of one Chinese pedigree and to identify the genotype-phenotype association, thereby facilitating the precise diagnosis of 21-OHD at the molecular level. Members of a Chinese family with 21-OHD were screened for mutations in the CYP21A2 gene. Clinical data and biochemical parameters, including androgen and derivatives, were collected. Complete DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) were utilized to analyze the genetic variations in the full-length CYP21A2 gene. A C-T transition located in exon 8 of the CYP21A2 gene, leading to the predicted amino acid residue change from Arg to Trp at codon 342, was identified in the mother and four sisters. Additionally, heterozygous deletion mutations of exons 1, 3, 4, 6 and 7 of paternal origin were detected in the four sisters by MLPA analysis. During the one-year follow-up, the four sisters exhibited symptom improvement following treatment with glucocorticoids, and the proband and one sister successfully conceived. The results of the present study demonstrated that novel compound heterozygous variations in the CYP21A2 gene may be causative agents of 21-OHD, providing insights into the functions of this gene and a more comprehensive understanding of the disorder.

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Lack of genotypephenotype correlation in congenital adrenal hyperplasia due to a CYP21A2-like gene

Cited by 5 publications

References 11 publications

<b><i>CYP21A2</i></b> Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

<b><i>CYP21A2</i></b> Gene Pathogenic Variants: A Multicenter Study on Genotype–Phenotype Correlation from a Portuguese Pediatric Cohort

A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics

Identification of a novel compound heterozygous mutation of the CYP21A2 gene causing 21‑hydroxylase deficiency in a Chinese pedigree

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