Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype–phenotype correlations

Zhang, Bo; Lü, Lin; Lü, Zhiyong

doi:10.1177/0300060516685204

Cited by 17 publications

(13 citation statements)

References 42 publications

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“…Among our 21-OHD CAH patients, the most prevalent CYP21A2 variants were c.293-13C > G (31.36%), Del (18.64%), p.I173N (16.95%), E3 Δ8 (5.08%), p.R483PfsX58 (4.24%) and p.R357W (3.39%). The rst three variants, c.293-13C > G, Del and p.I173N, were consistent with the most frequent variants in the Asian population [13][14][15][16][17]; however, our data showed higher E3 Δ8 and p.R483PfsX58 variant prevalence rates and a lower p.R357W variant prevalence. Ethnic differences were evident among different studies; the frequencies of p.P31L and p.V282L were 1.69% and 0.85% in our study, respectively, while the p.V282L…”

Section: Discussionsupporting

confidence: 84%

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Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Chang

Lü

Zhao

et al. 2020

Preprint

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Background: Primary adrenal insufficiency (PAI) is a life-threatening condition, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features.Methods: Seventy children were enrolled. Clinical information was collected, and combined genetic tests were performed according to the children’s manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants.Results: Among the 70 children, 84.29% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and a diagnosis of 21-hydroxylase deficiency (21-OHD) was subsequently genetically confirmed in 91.53% of the cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.10% (39/59), 30.51% (18/59), and 3.39% (2/59) of the cases, respectively. Interestingly, 17-hydroxyprogesterone (17-OHP) and testosterone levels in females were significantly higher than those in males among both SW and SV CAH patients. Additionally, 15.71% (11/70) of the patients were diagnosed with PAI, 72.73% (8/11) of whom had positive genetic findings. Among all the cases, two novel variants in CYP21A2, c.833dupT (p.279GfsX17) and c.651+2T>G, were harboured by CAH patients. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (p.108S>X, p.L411Vfs*6, c.1231_1234delCTCA, p.L411Vfs*6), 2 in the AAAS gene (c.399+1G>A, p.V103Afs*8, c.250delT, p.W84Gfs*10) and 1 in the NNT gene (p.I758Mfs*10), were detected. The novel variant c.399+1G>A in the AAAS gene was further confirmed to lead to exon 4 deletion in mRNA transcription and produce a truncated ALADIN protein.Conclusions: We found ethnic differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and testosterone levels, which warrants caution in relation to the virilization effect both physically and psychologically. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of paediatric PAI; however, further improvement of genetic testing tools beyond our protocol is still needed to uncover the complete aetiology of PAI in children.

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Section: Discussionsupporting

confidence: 84%

“…Surprisingly, we found that 8.47% (5/59) of the patients clinically presented with the SW (n = 4) and NC (n = 1) phenotypes without biallelic variants (Supplement Table 3). Studies have reported that the monoallelic variant and absent variants accounted for 2.2-24% of enrolled children [10,16,[19][20][21]26].…”

Section: Discussionmentioning

confidence: 99%

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Chang

Lü

Zhao

et al. 2020

Preprint

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“…Our global genotype–phenotype correlation was 92.4%, slightly higher than the average worldwide genotype–phenotype correlation, estimated in 80–90% [10, 11, 43]. Usually, the correlation is higher than 80–90% for the pathogenic variants associated with low enzymatic activity and a SW phenotype (groups 0 and A) and for the pathogenic variants of the group C (NC phenotype), but lower for the group B pathogenic variant (usually associated with a SV phenotype) [6, 9, 11-13, 24, 39, 44-46].…”

Section: Discussionmentioning

confidence: 58%

<b><i>CYP21A2</i></b> 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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“…It is worth mentioning that four out of five patients with P30L had clitoromegaly compared with none of those carrying other NC mutations (e.g., V281L) [53]. Clitoromegaly was also reported in NC patients carrying P30L in China [55]. This shows that the P30L mutation, although the enzyme activity is preserved sufficiently, causes a more severe form of NC or even a SV form.…”

Section: Molecular Structure Of P30l Mutation and Functional Analysismentioning

confidence: 96%

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020

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Despite numerous studies in the field of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, some clinical variability of the presentation and discrepancies in the genotype/phenotype correlation are still unexplained. Some, but not all, discordant phenotypes caused by mutations with known enzyme activity have been explained by in silico structural changes in the 21-hydroxylase protein. The incidence of P30L mutation varies in different populations and is most frequently found in several Central and Southeast European countries as well as Mexico. Patients carrying P30L mutation present predominantly as non-classical CAH; however, simple virilizing forms are found in up to 50% of patients. Taking into consideration the residual 21-hydroxulase activity present with P30L mutation this is unexpected. Different mechanisms for increased androgenization in patients carrying P30L mutation have been proposed including influence of different residues, accompanying promotor allele variability or mutations, and individual androgene sensitivity. Early diagnosis of patients who would present with SV is important in order to improve outcome. Outcome studies of CAH have confirmed the uniqueness of this mutation such as difficulties in phenotype classification, different fertility, growth, and psychologic issues in comparison with other genotypes. Additional studies of P30L mutation are warranted.

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Molecular diagnosis of Chinese patients with 21-hydroxylase deficiency and analysis of genotype–phenotype correlations

Cited by 17 publications

References 42 publications

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

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

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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