Novel nonsense mutation (W22X) in CYP21A2 gene causing salt-wasting congenital adrenal hyperplasia in a compound heterozygous girl

2007 ◽  
Vol 30 (9) ◽  
pp. 806-807 ◽  
Author(s):  
L. Di Pasquale ◽  
S. Indovina ◽  
M. Wasniewska ◽  
S. Mirabelli ◽  
P. Porcelli ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Nonsense Mutation ◽  
Compound Heterozygous ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Salt Wasting

scholarly journals ID: 1048 A novel nonsense mutation in the CYP21A2 gene of a Vietnamese patient with congenital adrenal hyperplasia

2017 ◽  
Vol 4 (S) ◽  
pp. 129
Author(s):  
Vu Chi Dung ◽  
Ngoc Lan Nguyen ◽  
Huy Hoang Nguyen ◽  
Thi Kim Lien Nguyen ◽  
Thinh Huy Tran ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Nonsense Mutation ◽  
Stop Codon ◽  
Large Deletion ◽  
Heterozygous Mutation ◽  
Normal Allele ◽  
Adrenal Hyperplasia ◽  
Steroid Synthesis ◽  
Cyp21a2 Gene ◽  
Exon 1

Inactivating mutations in the CYP21A2 gene which encodes the protein involved in steroid synthesis have been reported in the patients with congenital adrenal hyperplasia (CAH). An infant who diagnosed with the severe phenotype of CAH such as increasing testicular volume, elevating of 17-hydroxyprogesteron, testosterone and progesterone and his family were subjected for genetic studies. Initially, we used PCR and direct sequencing to screen mutations in the CYP21 gene in the proband and his family. We identified a novel nonsense mutation c.374C>G predicts a substitution of serine for a stop codon at codon 125 (p.S125*) within exon 3 in the proband. However, the inheritance pattern of the mutation was not consistent with disease causation because of a heterozygous mutation carrier in father and sibling, wild-type alleles in mother but mutant alleles in proband. This inspired us to find deletions of exon using multiplex ligation-dependent probe amplification (MLPA) assay. In the profiles of MLPA electropherogram, the proband had a large deletion in exon 3, but his mother did not have. It means that the proband inherited a normal allele from his mother and a mutant allele from his father, but the deletion of a normal allele occurred in the proband. Therefore, mutation c.374C>G (p.S125*) in exon 3 in the proband is considered as a heterozygous deletion mutation. In addition, a large deletion in exon 1 in the maternal allele in the proband is observed. Taking together, the proband carried a nonsense mutation accompanied with two deletions in exon 1 and exon 3 in the CYP21A2 gene affect the CAH phenotype severity. These mutations also expand the CYP21A2 mutation spectrum in CAH disorder. This case also highlights the need of caution when interpreting results of molecular genetics and biochemical testing during genetic counseling.

scholarly journals Tenascin-X, Congenital Adrenal Hyperplasia, and the CAH-X Syndrome

2018 ◽  
Vol 89 (5) ◽  
pp. 352-361 ◽  
Author(s):  
Walter L. Miller ◽  
Deborah P. Merke
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Matrix Protein ◽  
Connective Tissue Disorder ◽  
Joint Hypermobility ◽  
Extracellular Matrix Protein ◽  
Adrenal Hyperplasia ◽  
Full Spectrum ◽  
Ehlers Danlos Syndrome ◽  
Cyp21a2 Gene ◽  
Salt Wasting

Mutations of the CYP21A2 gene encoding adrenal 21-hydroxylase cause congenital adrenal hyperplasia (CAH). The CYP21A2 gene is partially overlapped by the TNXB gene, which encodes an extracellular matrix protein called Tenascin-X (TNX). Mutations affecting both alleles of TNXB cause a severe, autosomal recessive form of Ehlers-Danlos syndrome (EDS). Rarely, patients with severe, salt-wasting CAH have deletions of CYP21A2 that extend into TNXB, resulting in a “contiguous gene syndrome” consisting of CAH and EDS. Heterozygosity for TNXB mutations causing haploinsufficiency of TNX may be associated with the mild “hypermobility form” of EDS, which principally affects small and large joints. Studies of patients with salt-wasting CAH found that up to 10% had clinical features of EDS, associated joint hypermobility, haploinsufficiency of TNX and heterozygosity for TNXB mutations, now called “CAH-X.” These patients have joint hypermobility and a spectrum of other comorbidities associated with their connective tissue disorder, including chronic arthralgia, joint subluxations, hernias, and cardiac defects. Other disorders are beginning to be associated with TNX deficiency, including familial vesicoureteral reflux and neurologic disorders. Further work is needed to delineate the full spectrum of TNX-deficient disorders, with and without associated CAH.

Detection of a novel severe mutation affecting the CYP21A2 gene in a Chilean male with salt wasting congenital adrenal hyperplasia

Endocrine ◽  
2019 ◽  
Vol 67 (1) ◽  
pp. 258-263
Author(s):  
Eugenio Arteaga ◽  
Felipe Valenzuela ◽  
Carlos F. Lagos ◽  
Marcela Lagos ◽  
Alejandra Martinez ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Salt Wasting ◽  
Severe Mutation

scholarly journals Non-Classical Congenital Adrenal Hyperplasia-Causing Alleles in Adolescent Girls with PCOS and in Risk Group for PCOS Development

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 980
Author(s):  
Lasma Lidaka ◽  
Laine Bekere ◽  
Gunta Lazdane ◽  
Iveta Dzivite-Krisane ◽  
Anda Kivite-Urtane ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Control Group ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Female Population ◽  
Increased Risk

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. Depending on the diagnostic criteria applied, it occurs in up to 16.6% of the general female population. Congenital adrenal hyperplasia includes a group of autosomal recessive disorders, the most common of which is non-classical congenital adrenal hyperplasia (NCAH) caused by mutations in the CYP21A2 gene. PCOS and NCAH have similar clinical manifestations (hyperandrogenemia, i.e., hirsutism, acne, alopecia, and increased androgen levels in the blood) and potential impact on long-term health (infertility, increased risk of type 2 diabetes, and cardiovascular disease. Consequently, it is thought that NCAH mutations in the heterozygous state may play a role in PCOS development and phenotypic expression. Objective: To determine the prevalence of the most common pathogenic alleles of the CYP21A2 gene in adolescents with PCOS and adolescents at risk of PCOS development, and to compare the results with healthy adolescents matched for gynecological age. Methods: A cross-sectional study was conducted with 55 PCOS patients, 23 risk patients (with hyperandrogenism but a normal menstrual cycle), and 49 healthy adolescents. Genetic variations in the CYP21A2 gene were analyzed using a standard Multiplex Ligation-dependent Probe Amplification test (SALSA MLPA Probemix P050-C1 CAH; MRC Holland). Results: No significant differences were found among the three groups regarding the frequency of carriers of NCAH variations in the heterozygous state. It was found that the I172N carrier in the PCOS group had a significantly higher Global Acne Grading Scale score than PCOS patients without this variation (p = 0.038). Within the control group of healthy adolescents, compound heterozygous carriers (IVS2-12A > G and -113G > A) had a significantly higher body mass index than non-carriers (p = 0.036). Conclusion: We found no differences in the incidence of NCAH-causing variations in the heterozygous state in adolescent PCOS patients, risk adolescents (with hirsutism but normal menstruation), and healthy adolescents. Future studies of larger cohorts and rarer pathogenic CYP21A2 gene variations are required.

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

2019 ◽  
Vol 51 (09) ◽  
pp. 586-594 ◽  
Author(s):  
Vassos Neocleous ◽  
Pavlos Fanis ◽  
Meropi Toumba ◽  
Charilaos Stylianou ◽  
Michalis Picolos ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Salt Wasting ◽  
Greek Cypriot ◽  
Frequent Mutations ◽  
Simple Virilizing ◽  
21 Hydroxylase Deficiency ◽  
Greek Cypriots

AbstractCongenital 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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