Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency

Abstract

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 are 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 in order 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, six 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 six 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.

Aldosterone synthase (CYP11B2) deficiency among Palestinian infants: Three novel variants and genetic heterogeneity

“…Similarly, a recent manuscript about a large cohort of 62 patients mostly of Greek origin also found a founder effect in regard to ASD in this population. A previously reported p.T185I variant was found in 96% of the patients (Merakou et al, 2020). In comparison to these reports, our patients had similar clinical presentation with early infantile onset of vomiting, dehydration, failure to thrive, hyponatremia and hyperkalemia.…”

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency

“…Based on the location of the variant, in close proximity to two earlier described pathogenic variants ( 17 ), the known deleterious effect of the variant in the highly homologous CYP11B1 gene ( 19 ), the low frequency in the gnomAD database, the results of prediction programs, the results of protein modeling and the appropriate clinical and biochemical findings in the proband, strongly suggest this variant to be pathogenic, in our opinion.…”

“…As demonstrated in the present case, increased levels of mineralocorticoid precursors before the enzymatic block may be found. Clinically, the disease manifests in the neonatal period or early infancy with vomiting, dehydration, and failure to thrive ( 16 , 17 , 18 ). These symptoms are nonspecific and can easily be mistaken for more common conditions .…”

“…To date, more than forty different pathogenic variants in the CYP11B2 gene causing isolated aldosterone synthase deficiency have been reported, most of which are missense and nonsense variants that greatly compromise enzymatic activity ( 17 , 18 ). In a recent study, the missense variant c.554C>T p.(Thr185Ile) was found, either in a homozygous or compound heterozygous state, in the vast majority of the studied patients ( 17 ). To the best of our knowledge, the missense variant c.400G>A p.(Gly134Arg) detected in the proband and his family members has not been described before.…”

Use of Genomics to Develop Novel Therapeutics and Personalize Hypertension Therapy

“…An example of this is variants in the CYP11B2 gene encoding aldosterone synthase, which have been associated with rare clinical presentations of hypoaldosteronism, associated with salt wasting and low BP. 61 Candidate gene studies have associated polymorphisms in CYP11B2 with renal sodium handling and left ventricular hypertrophy. 62 In contrast to MRAs, ASIs reduce the aldosterone levels with no likely impact on the mineralocorticoid receptor-independent nongenomic pathways.…”