Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India

Gangodkar, Priyanka; Khadilkar, Vaman; Raghupathy, P.; Kumar, Rakesh; Dayal, Archana Arya; Dayal, Devi; Ayyavoo, Ahila; Godbole, Tushar; Jahagirdar, Rahul; Bhat, Kavitha; Gupta, Neerja; Kamalanathan, Sadishkumar; Jagadeesh, Sujatha; Ranade, Shatakshi; Lohiya, Nikhil; Oke, Rashmi Lote; Ganesan, Karthik; Khatod, Kavita; Agarwal, Meenal; Phadke, Nikhil; Khadilkar, Anuradha

doi:10.1007/s12020-020-02494-z

Cited by 23 publications

(14 citation statements)

References 33 publications

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“…Compared with previous northern Indian published studies, none of our present cohorts had p.Arg340His mutation. [ 9 10 ] The high frequency of p.Pro31Leu mutations in this study is similar to the other published literature from India. The most common mutations identified in the other published Indian studies were Intron 2 (c.293-13A/C>G) mutation, p.Pro31Leu, and p.Ile173Asn.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, the prevalence of the above mutations is similar to the previously published studies from India. [ 8 9 10 11 ]…”

Section: Discussionmentioning

confidence: 99%

“…The most common mutations identified in the other published Indian studies were Intron 2 (c.293-13A/C>G) mutation, p.Pro31Leu, and p.Ile173Asn. [ 8 9 10 11 ] More than 90% of mutant alleles carry one or more of a discrete number of mutations, if no mutations are detected, we may assume that the individual is unaffected. The reasons for difference in mutation prevalence among different studies were due to the degree of consanguinity, ethnicity, availability of newborn screening, varied time of presentation as SW/SV, and nonclassic nature of disease.…”

Section: Discussionmentioning

confidence: 99%

“…[ 5 ] There are only six studies that had reported the spectrum and frequency of the CYP21A2 gene mutations in the Indian population. [ 6 7 8 9 10 11 ] Except for the recently published one,[ 11 ] there is a lack of data on the clinical profile and spectrum of mutations in the south Indian CAH population. In addition, there was a wide spectrum of clinical presentation among different ethnicities and a lack of phenotype-genotype correlation.…”

Section: Introductionmentioning

confidence: 99%

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The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation

Sridhar¹,

Soundian²,

Poomarimuthu³

et al. 2021

Indian Journal of Endocrinology and Metabolism

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Aim: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the adrenal steroidogenic pathway. The most common form of CAH is due to 21-hydroxylase deficiency resulting from mutations in CYP21A2 gene. The present study aimed to identify CYP21A2 common gene mutations, phenotype correlation, and to analyze the segregation pattern in CAH patients, parents, and siblings. Materials and Methods: Sixteen families having at least one classic CAH child in each family, a total of 58 subjects were recruited. The presence of six most common gene mutations, namely, Intron 2 (c.293-13A/C>G), c.844G>T (p.Val282Leu), c.1019G>A (p.Arg340His), c.92C>T (p.Pro31Leu), c.955C>T (p.Gln319*), and c.518T>A (p.Ile173Asn) in CYP21A2 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using specific primers. Results: Out of 16 classic CAH females analyzed, salt-wasting (SW) form was present in 12 (75%) and simple virilizing form in four (25%) children. Isolated clitoromegaly was the most common clinical presentation followed by ambiguous genitalia. The most common mutation observed in CAH patient population was Intron 2 (c.293-13A/C>G) (100%) followed by p.Pro31Leu (98%), p.Gln319* (93%), p.Val282Leu (91.4%), and p.Ile173Asn (19%). Although p.Arg340His mutation was not observed in this study. Interestingly, Intron 2 (c.293-13A/C>G) homozygous was observed in 31.3% of the entire study cohort and p.Ile173Asn mutation was found to be associated with SW form. Conclusions: Our results suggested a high prevalence of CYP21A2 gene mutations among CAH patients and heterogeneous mutation spectrum in their families of south Indian cohort. The outcomes afford valuable evidence for premarital and prenatal screening as well as planning suitable programs to prevent the development of CAH in Indian population.

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Section: Discussionsupporting

confidence: 90%

“…Moreover, the prevalence of the above mutations is similar to the previously published studies from India. [ 8 9 10 11 ]…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation

Sridhar¹,

Soundian²,

Poomarimuthu³

et al. 2021

Indian Journal of Endocrinology and Metabolism

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“…A few years ago, this technology was not applied to screen the CYP21A2 gene defects due to its high sequence identity with CYP21A2P which hampers the proper analysis of this genomic region 5 . However, recently some groups have found alternative ways to perform NGS for the CYP21A2 gene through a combination with other methods, such as Multiplex ligation-dependent probe amplification 8,9 . These genetic analysis strategies of the CYP21A2 gene with the NGS technology represent a promising tool for the future, opening the window to identify new variants while improving the diagnosis of CYP21A2 deficiency, and establishing a more reliable estimate of mutation frequencies.…”

Section: Introductionmentioning

confidence: 99%

Meta analysis of variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2

Prado

Ligabue-Braun

Zaha

et al. 2021

Preprint

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Context: CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Objective: Analyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2. Methods: SNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. Results: SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews' correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). Conclusion: From our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs' in CYP21A2.

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Genetics of Congenital Adrenal Hyperplasia

Rao,

Walia

2024

Children With Differences in Sex Development

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Clinical application of a novel next generation sequencing assay for CYP21A2 gene in 310 cases of 21- hydroxylase congenital adrenal hyperplasia from India

Cited by 23 publications

References 33 publications

The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation

The Spectrum of CYP21A2 Gene Mutations from 16 Families of Congenital Adrenal Hyperplasia: Genotype-Phenotype Correlation

Meta analysis of variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2

Genetics of Congenital Adrenal Hyperplasia

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