THE VARIETY OF GENETIC DEFECTS EXPLAINS THE PHENOTYPIC HETEROGENEITY AND THE MODE OF TRANSMISSION OF FAMILIAL HYPERKALEMIC HYPERTENSION

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Abstract Objective: Familial Hyperkalemic Hypertension (FHHt) is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, interacting together in the regulation of ion transport in the distal renal tubule. Whether the type of variants and mutated gene explains the large phenotypic heterogeneity and the different modes of transmission in FHHt has not been explored yet. We report herein the experience of a referral centre based on 151 molecularly proven FHHt cases (82 probands, 69 relatives). Design and method: Patients with persistent hyperkalemia without renal failure, associated with metabolic acidosis, were genetically explored by Sanger sequencing and by new generation sequencing (NGS)Identified variants were confirmed and classified according to the American College of medical Genetics. Clinical and biological data were analyzed based on “questionnaires” filled out by the prescribing physicians. Statistical analyzes were done using Kruskal-Wallis test and post hoc Dunn's multiple comparison tests using Prism V6. Results: We identified 16 families with 12 different CUL3 splice-site variants, 48 families with 37KLHL3 variants (13 in recessive form, 24 in dominant form), 4 families with 4 different WNK1 intron 1 deletions, 11 families with 6 variants in the WNK1 acidic motif and 4 families with 4 different variants in the WNK4 acidic and basic motifs (figure 1). De novo cases were mainly observed in the CUL3-related cases (9 out of 16), recessive cases were only observed in few KLHL3-related cases (13 out 48), whereas all others variants were transmitted in an autosomal dominant manner. The more severe and earlier cases were caused by KLHL3 homozygous variants and CUL3 heterozygous variants in this case associated with growth retardation. Patients with WNK1 acidic motif variants had a typical biological phenotype without hypertension conversely to WNK4 mutations affecting the same motif. Molecular familial screening of relatives allowed us to detect 69 positive cases. Whatever the causing gene, administration of hydrochlorothiazide was effective. Conclusions: This study reinforces the interest of a genetic screening in case of suspicion of FHHt to better orientate the medical care of the patient and his family