Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in SCNN1A, SCNN1B or SCNN1G, which respectively encode the alpha, beta and gamma subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole-exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co-segregation analysis was conducted. A frameshift mutation in SCNN1B (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early-onset hypertension and hypokalemia. The mutation led to the truncation of the beta subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow-up data from patients with Liddle syndrome with SCNN1B mutations was performed. The follow-up data of 108 patients with pathogenic SCNN1B mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early-onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.

Objective: Liddle syndrome is an autosomal dominant form of monogenic hypertension caused by mutation of the SCNN1A, SCNN1B, and SCNN1G genes, which respectively encode various subunits of the epithelial sodium channel. In this report, we describe a frameshift mutation in SCNN1B in a Chinese family with early-onset hypertension and hypokalemia. Design and method: DNA was extracted from leucocytes in peripheral blood obtained from all family members. Whole-exome sequencing and Sanger sequencing were performed to verify the candidate variant and conduct co-segregation analysis. We also reviewed the clinical and biochemical characteristics of patients with the same mutation described in the literature and performed a genotype–phenotype correlation analysis. Results: Whole-exome sequencing identified a c.1806dupG frameshift variant in SCNN1B leading to substitution of alanine for proline at position 603 and premature emergence of a stop codon at position 607. Phenotypic heterogeneity is evident in patients with the mutation reported in the literature and is reflected in the proportions with hypertension (94.4%), hypokalemia (58.9%), hypoaldosteronemia (52.9%), and hyporeninemia (41.1%). Patients with the mutation have a good response to targeted ENaC inhibitor therapy. Conclusions: We have identified a frameshift mutation (c.1806dupG) in SCNN1B in a Chinese family characterized by early-onset hypertension and hypokalemia. Confirmatory genetic testing is necessary and targeted therapy should be used to prevent premature onset of clinical endpoints events in patients suspected to have mutation. Genotype-phenotype correlation analysis involving the P603 residue variant provides further evidence of phenotypic heterogeneity and guidance for clinical management of Liddle syndrome.

Hypertension is a cardiovascular disease that seriously threat-ens public health worldwide.Early and effective control of blood pressure can prevent the occurrence of stroke,coronary heart dis-ease,kidney disease,etc.[1,2].The influence of genetic factors on hypertension has been confirmed multiple times,and targeted medication according to genetic testing remains a challenge for hypertension treatment at present[3].

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular disease involving small-to-medium-sized arteries. The characteristics of Chinese patients with FMD remain unclear. We retrospectively analyzed the data of patients with renal FMD who underwent percutaneous transluminal renal angioplasty (PTRA) for the first time at Fuwai Hospital between 2010 and 2021. The variables were selected through least absolute shrinkage and selection operator regression (LASSO), and logistic regression models were constructed to identify independent risk factors. A total of 116 patients (52 males, median age at diagnosis, 25.0 years) were enrolled. Elevated blood pressure was the leading complaint. After a median follow-up period of 18.0 months (interquartile range: 6.0–48.0 months), hypertension recurred in 34 patients and restenosis in nine patients, among whom four patients underwent secondary intervention and one patient underwent surgical revascularization. Bilateral renal artery involvement (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.11–6.15; p = 0.028) and age at hypertension onset (OR: 0.93, 95% CI: 0.88–0.99; p = 0.018) were independent prognostic factors for adverse outcomes. The results indicate that patients with bilateral renal artery involvement and younger age at hypertension onset are more likely to have poorer clinical outcomes after PTRA, and should be more closely monitored.

BACKGROUND:Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described.METHODS:Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further.RESULTS:Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events.CONCLUSIONS:The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

BACKGROUND:Left ventricular noncompaction (LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family.METHODS:A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband (I-2), the proband's daughter (II-1, affected) and mother (III-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members.RESULTS:Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin (OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools.CONCLUSIONS:Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin's roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.

Background:Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, β, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family.Methods:DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism.Results:We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome.Conclusion:c.1691_1693delinsG, a novel frame-shift mutation in the β subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with a strong genetic background.The symptoms of patients are mostly related to excessive release of catecholamines.In recent years, related scholars have made a lot of progress in the potential pathogenesis of PPGLs such as heredity, metabolism, and immunity, which provides a theoretical basis for the further diagnosis and treatment of PPGLs.With the discovery of pathogenic genes of PPGLs, people have a new understanding of the treatments, prognosis and follow-up of PPGLs.This article reviews the molecular genetics of PPGLs.

Background: Neurofibromatosis type 1 (NF-1) is a common autosomal dominant disorder caused by mutations in the NF1 gene. It is characterized by multiple café-au-lait macules, cutaneous neurofibromas, optic glioma, Lisch nodules, and axillary and inguinal freckling. The aim of this study was to investigate NF1 mutations in two Chinese families with NF-1 who presented with early-onset hypertension, and to determine the prevalence of hypertension associated with NF-1 to better understand this complication.Methods: Whole-exome sequencing was performed for the probands with NF-1 from two unrelated families. Possible pathogenic mutation was predicted by bioinformatic tools. Sanger sequencing was used to confirm candidate variants in all available individuals for familial co-segregation analysis. We also performed a systematic literature review of studies that reported the prevalence of hypertension in patients with NF-1.Results: In family 1, a recurrent mutation c.6789_6792delTTAC in NF1 was identified in the proband but in no other family members, indicating that this is a de novo mutation. In family 2, a novel mutation c.6934_6936delGCAinsTGCT in NF1 was detected in the proband and two other family members, which co-segregated with the disease phenotype within the family. Both mutations were predicted to be pathogenic by bioinformatic analysis. We found hypertension was a relatively common complication of NF-1, with a prevalence range of 6.1–23.4%. Ambulatory blood pressure monitoring is a stable method for detecting initial alterations of the blood pressure pattern, particularly for pre-hypertension.Conclusions: We identified one recurrent (c.6789_6792delTTAC) and one novel frame-shift mutation (c.6934_6936delGCAinsTGCT) in two unrelated families with NF-1 using whole-exome sequencing. In consideration of phenotypic heterogeneity in NF-1, genetic testing is a robust tool which helps early and accurate diagnosis. Because hypertension is not a rare complication of NF-1, routine screening for hypertension in patients with NF-1, especially children and adolescents, is important to avoid serious cardiovascular events.