Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve

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 cardiomy-opathy(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 coexist-ent 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 dia-gnosis 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%,re-spectively,for BAV with HCM,DCM and LVNC.During the index hospitalization,24 of the 57 patients(42.1%)underwent sur-gery,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 popula-tion.Aortopathy and heart failure were common,with almost half of patients requiring surgery at diagnosis.

A novel missense mutation in obscurin gene in a Chinese consanguineous family with left ventricular noncompaction

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.