Dataset Information

A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population.

ABSTRACT:

Context

Pseudohypoaldosteronism (PHA) is a condition in which serum aldosterone level is normal or elevated but its action is deficient.

Objective

This study describes the molecular genetics of PHA 1b in the highly consanguineous population of 2 Arabian Gulf countries, Saudi Arabia and Oman.

Methods

This study enrolled 22 patients from 13 unrelated families (2 families with 5 patients from Oman and 11 families with 17 patients from Saudi Arabia). All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension. We isolated DNA from peripheral blood and PCR-sequenced all exons and exon-intron boundaries of SCNN1A and, if negative, SCNN1B and SCNN1G using the Dideoxy Chain termination method.

Results

We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G. All of these mutations were novel except one. SCNN1A mutations were: c.1496A>G, p.Q499R (novel) in 1 patient; c.1453C>T, p.Q485X (novel) in 1 patient; c.1322_1322delA, p.N441Tfs*41 (novel) in 2 patients of 1 family; c.876 + 2 delGAGT (novel) in 3 patients of 1 family; c.203_204 delTC, p.I68Tfs*76 (a known mutation) in 8 patients of 5 families; and whole SCNN1A gene deletion (novel) in 2 patients of 2 families. In addition, a nonsense SCNN1B mutation c.1694C>A, p.S565X (novel) was found in 3 siblings from 1 Omani family, and an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family.

Conclusion

We characterized a unique genotype of PHA 1b with several novel gene structure-disrupting mutations in SCNN1A, SCNN1B, and SCNN1G in a highly consanguineous population.

SUBMITTER: Alzahrani AS

PROVIDER: S-EPMC8272535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UNLABELLED:Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1?mmol/l (reference range: 3.4-5.1?mmol/l), aldosterone 2800?ng/dl (reference range: ?21?ng/dl) and plasma renin activity 90?ng/ml/h (reference range: 0.6-4.3?ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia. LEARNING POINTS:PHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment.