ECE2024 Eposter Presentations Adrenal and Cardiovascular Endocrinology (155 abstracts)
Phenotype variability in intron2 splice variant of CYP21A2 gene – a single-centre pilot study on children and adolescents
Iuliana Gherlan 1,2 , Procopiuc Cameliua 2 , Madalina Vintila 1,2 , Radomir Lidia 2 , Andreea Cristiana Brehar 2 , Elena Braha 2 , Suzana Vladoiu 2 , Dana Manda 2 , Andrei Muresan 2 , Poalelungi Catalina 2 & Sorina Schipor 2
1Carol Davila University of Medicine and Pharmacy, București, Romania; 2C.I. Parhon National Institute of Endocrinology, București, Romania
Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is caused by mutations in the CYP21A2 gene, located on the short arm of chromosome 6. Approximately 11 point mutations are responsible for over 90% of cases, with good genotype-phenotype correlations. Depending on the residual 21-hydroxylase activity, three distinct phenotypes (classic salt wasting – SW, classic simple virilising – SV and non-classic - NC) with 4 corresponding genotypes have been described (null, A, B, C). Although usually associated with SW forms, higher variability in phenotype has been described in patients with intron 2 (I2) splice (c.293-13A>G) variant.
Aim: To describe the genotype-phenotype correlation in 21OHD patients with I2 splice variant.
Methods: Between January 2021 and December 2023, 40 children and adolescents with 21-hydroxylase deficiency referred to our centre were clinically and genetically characterised. Multiple ligation-dependent probe amplification (MLPA) method using the MRC-Holland SALSA MLPA P050-C1 kit and Coffalyser.net software were used for the evaluation of copy number variations and several point mutations of the CYP21A2 gene. We used Sanger sequencing (CEQ 8000 Genetic Analysis System, Beckman Coulter) to confirm these variants and to analyse the entire gene sequence in probands and their parents.
Results: I2 splice variant was described in 11 patients (27.5% of 21OHD patients) for a total of 17 alleles (21.25% of all alleles). It was observed in 5 patients in a homozygous state and in another 6 patients in a compound heterozygous state. From the homozygous patients, 3 cases were clinically SW, and the other 2 related patients were clinically expressing NC CAH. The compound heterozygous patients had the same predicted and observed salt-wasting phenotype in patients with I2 splice/p.Arg357Trp and I2 splice/p.Gln319Ter genotype. A case with an expected SV predicted phenotype (I2 splice/p.Ile173Asn genotype) had the same clinically expressed one. The association between I2 splice on one allele and p.Pro454Ser and p.Pro31Leu on the other one led to a predicted NC phenotype, but SV-type clinical manifestations. Instead, patients with I2 splice/p.Pro454Ser and I2 splice/p.Pro31Leu, p.Val282Leu had the same predicted and observed NC phenotype. As a result, the relative frequency of predicted phenotype is 0.71 for SW, 1 for SV and 0.66 for NC phenotype, respectively.
Conclusion: In our group of patients I2 splice allele had a similar incidence to other European populations and a good genotype-phenotype correlation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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