TY - JOUR
TI - Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency
AU - Merakou, C.
AU - Fylaktou, I.
AU - Sertedaki, A.
AU - Dracopoulou, M.
AU - Voutetakis, A.
AU - Efthymiadou, A.
AU - Christoforidis, A.
AU - Dacou-Voutetakis, C.
AU - Chrysis, D.
AU - Kanaka-Gantenbein, C.
JO - JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
PY - 2021
VL - 106
TODO - 1
SP - E182-E191
PB - Endocrine Society
SN - 0021-972X
TODO - 10.1210/clinem/dgaa765
TODO - adenine;  alanine;  aldosterone synthase;  arginine;  cysteine;  glutamine;  guanine;  methionine;  threonine;  valine;  aldosterone synthase, aldosterone synthase deficiency;  Article;  autosomal recessive disorder;  child;  cohort analysis;  computer model;  controlled study;  CYP11B2 gene;  gene amplification;  gene sequence;  genetic variability;  genotype;  heterozygosity;  homozygosity;  human;  hypoaldosteronism;  infant;  intron;  major clinical study;  molecular diagnosis;  molecular genetics;  newborn;  pathogenesis;  pathogenicity;  preschool child;  protein stability;  school child;  sibling;  tertiary care center;  Addison disease;  dna mutational analysis;  female;  genetic association study;  genetics;  Greece;  heterozygote;  homozygote;  hypoaldosteronism;  male;  mutation, Addison Disease;  Cohort Studies;  Cytochrome P-450 CYP11B2;  DNA Mutational Analysis;  Female;  Genetic Association Studies;  Greece;  Heterozygote;  Homozygote;  Humans;  Hypoaldosteronism;  Infant;  Infant, Newborn;  Male;  Mutation
TODO - Context: Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. Objective: To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. Design: Clinical and molecular study. Setting: Tertiary academic Children's Hospital, Center for Rare Pediatric Endocrine Diseases. Patients and Methods: Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. Results: CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. Conclusion: Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene. © 2020 The Author(s).
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