Mosaicism for KCNJ5 Causing Early-Onset Primary Aldosteronism due to Bilateral Adrenocortical Hyperplasia

Abstract

Background Somatic variants in KCNJ5 are the most common cause of primary aldosteronism (PA). There are few patients with PA in whom the disease is caused by germline variants in the KCNJ5 pottasium channel gene (familial hyperaldosteronism type III – FH-III). Methods A 5 year-old patient who developed hypertension due to bilateral adrenocortical hyperplasia (BAH) causing PA had negative peripheral DNA testing for any known genetic causes of PA. He was treated medically with adequate control of his PA but by the third decade of his life, due to worsening renal function, he underwent bilateral adrenalectomy. Results Focused exome sequencing in multiple nodules of his BAH uncovered a “hot-spot” pathogenic KCNJ5 variant, while repeated Sanger sequencing showed no detectable DNA defects in peripheral blood and other tissues. However, whole exome, “deep” sequencing revealed that 0.23% of copies of germline DNA did in fact carry the same KCNJ5 variant that was present in the adrenocortical nodules, suggesting low level germline mosaicism for this PA-causing KCNJ5 defect. Conclusions Thus, this patient represents the first to our knowledge case of BAH due to a mosaic KCNJ5 defect. Undoubtedly, his milder PA compared to other known cases of FH-III, was due to his mosaicism. This case has a number of implications for the prognosis, treatment and counseling of the many patients with PA due to BAH that are seen in hypertension clinics.

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

“…CTNNB1 mosaicism has occasionally been suggested, and much further work is required to determine whether mosaicism for either or both genes might be the antecedent to double-mutant APAs 62,63 . A case of KCNJ5 mosaicism was recently reported 64 .…”

Transcriptomic uniqueness and commonality of the ion channels and transporters in the four heart chambers

“…Point mutations of this channel (a.k.a. GIRK4 or KATP1) may result in a peculiar type of long QT syndrome (LQT-13), as well as in familial hyperaldosteronism type III 50 . Kcnq1 encoding Kv7.1 or KvLQT1, the ion channel contributing the slow component of the cardiac delayed rectifier K + current I Ks , is also preferentially expressed in atria.…”

Genetics of Primary Aldosteronism

“… 52 Evidence from germline KCNJ5 mutations (see below) and, specifically individuals with mosaicism for KCNJ5 mutations suggest that these mutations either increase proliferation or block transdifferentiation, leading to hyperplasia in vivo. 50 , 53 , 54 APA-associated ATPA1A1 mutations would likely be lethal if present in the germline. However, a recent study provided evidence for proliferative effects of an ATPA1A mutation in the HAC15 adrenocortical cancer cell line in vitro, an effect that was serum dependent.…”