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: KLHL3 (n = 50), CUL3 (n = 16), WNK1 acidic motif (n = 11), WNK4 acidic motif (n = 4) and WNK1 intron 1 deletions (n = 3). De novo cases were mainly observed in the CUL3-related cases (9 of 12) and recessive cases were only observed in KLHL3-related cases (14 of 50). More severe forms were observed in recessive KLHL3 and CUL3 cases that were also associated with growth retardation. Patients with WNK1 acidic motif variants had a typical biological phenotype and lower frequency of hypertension conversely to WNK4 variants affecting the same motif. Patients with heterozygous KLHL3 and WNK1 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 CUL3 and recessive KLHL3 genotypes through intermediate forms associated with KLHL3 dominant, WNK4 and WNK1 deletion to mild form associated with WNK1 acidic motif genotype and reinforces the interest of genetic screening to better orientate medical care and genetic counseling.

Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum.

PURPOSE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to skin, eye, and cardiovascular manifestations with considerable phenotypic variability of unknown cause. We aimed to identify genotype-phenotype correlations in PXE. METHODS: A molecular analysis was performed on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Variant topographic analysis and genotype-phenotype correlation analysis were performed according to the number and type of identified variants. RESULTS: Complete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6. For the 220 cases with a complete PS, there was a higher prevalence of eye features in Caucasian patients (P = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (P = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11 and 10%, respectively). CONCLUSION: We propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients.Genet Med advance online publication 19 January 2017.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations.

BACKGROUND AND OBJECTIVES: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed. RESULTS: Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression. CONCLUSIONS: Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.