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 dis-ease 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, af-fected) 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 mis-sense 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 dif-ferent 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 cardiomy-opathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.

Xue-Qi DONG;Pei-Pei QIN;Di ZHANG;Qiong-Yu ZHANG;Yi QU;Lin ZHAO;Yi-Ting LU;Yu-Xiao HU;Chun-Xue YANG;Xin-Chang LIU;Ya-Xin LIU;Xian-Liang ZHOU

Department of Cardiology,Fuwai Hospital,National Center for Cardiovascular Disease,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China;Department of Obstetrics and Gynecology,Peking Union Medical College Hospital,Beijing,China

老年心脏病学杂志（英文版）

[1]Xue-Qi DONG;Pei-Pei QIN;Di ZHANG;Qiong-Yu ZHANG;Yi QU;Lin ZHAO;Yi-Ting LU;Yu-Xiao HU;Chun-Xue YANG;Xin-Chang LIU;Ya-Xin LIU;Xian-Liang ZHOU-.A novel missense mutation in obscurin gene in a Chinese consanguineous family with left ventricular noncompaction)[J].老年心脏病学杂志（英文版）,2022(07):531-538

obscurin,proband,OBSCN,C19063T,R6355W,cardiomyopathies,uninterpreted,cardiomy,opathies

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