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.

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.

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.

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.

Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies.

The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart.

A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes.

The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin’s roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

To analyze the causes of renal artery stenosis (RAS) and compare the clinical characteristics in accordance with the primary disease among patients aged from 30 to 50.

Patients were grouped by etiologies of RAS. Groups were retrospectively examined and compared regarding demographic data, clinical manifestations, laboratory findings, and imaging findings.

A total of 152 patients (74 females, 78 males; mean age: 40.70 ± 6.01 years) were enrolled, including 84 patients (55.3%) with atherosclerosis (AS), 46 patients (30.3%) with Takayasu arteritis (TA), 18 patients (11.8%) with fibromuscular dysplasia (FMD), and four patients (2.6%) with other etiologies. Patients in AS group had greater body mass index, higher prevalence of comorbidities and higher rate of smoking and drinking history. TA patients showed more constitutional symptoms and vascular findings, and higher erythrocyte sedimentation rate. RAS in both AS group and TA group mainly located on ostia and proximal segments, but RAS in FMD group mainly involved middle to distal segment of renal artery. The AS group had significantly lesser stenosis than the other groups. Although renal function evaluated by the estimated glomerular filtration rate did not significantly differ among the groups, the incidence of kidney shrinkage was significantly higher in the TA and FMD groups (39.1% and 50%, respectively) than in the AS group (8.3%). The FMD group had milder cardiac damage than other groups.

AS was the most common cause of RAS in patients aged from 30 to 50, followed by TA and FMD. The etiology of RAS should be carefully distinguished based on clinical manifestations, laboratory findings, and imaging to ensure that proper treatment is provided.