The variety of genetic defects explains the phenotypic heterogeneity of Familial Hyperkalemic Hypertension.

Introduction: Familial hyperkalemic hypertension is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, the variants of these genes cause disruption in the regulation of ion transport in the distal renal tubule. Whether the genotype explains the large phenotypic heterogeneity has not been fully explored.

Methods: We retrospectively analyzed clinical and genetic data of 153 cases (84 probands, 69 relatives) with familial hyperkalemic hypertension.

Results: Pathogenic variants (25 novel variants) were identified as follows: (n = 50), (n = 16), acidic motif (n = 11), acidic motif (n = 4) and intron 1 deletions (n = 3). cases were mainly observed in the -related cases (9 of 12) and recessive cases were only observed in -related cases (14 of 50). More severe forms were observed in recessive and cases that were also associated with growth retardation. Patients with acidic motif variants had a typical biological phenotype and lower frequency of hypertension conversely to variants affecting the same motif. Patients with heterozygous and deletions had milder forms. Familial screening in 178 relatives allowed detection and care for 69 positive cases. Blood pressure and hyperkalemia were improved by hydrochlorothiazide in all groups.

Conclusions: This study confirms the phenotypic variability ranging from the severe and early forms associated with and recessive genotypes through intermediate forms associated with dominant, and deletion to mild form associated with acidic motif genotype and reinforces the interest of genetic screening to better orientate medical care and genetic counseling.