Homozygous SGCB splice-site variant causes isolated dilated cardiomyopathy through sarcoglycan complex destabilization in East Asians

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Abstract

Dilated cardiomyopathy (DCM) is a genetically heterogeneous disorder, characterized by ventricular dilatation and impaired systolic function, leading to heart failure and sudden cardiac death. Despite advances in genomic technologies, the genetic cause of DCM remains unidentified in more than half of the cases. Here, we performed an integrative analysis of genomic and transcriptomic data from patient-derived cardiac tissue to identify causative variants in genetically undiagnosed DCM. This approach enabled us to identify a homozygous splice-site variant (c.243+6T>A) in the sarcoglycan gene SGCB, which results in exon 2 skipping. This variant was significantly enriched in patients with DCM compared with the general population, with consistent genotype–phenotype correlations observed across multiple families. Protein-level analysis of cardiac tissue from homozygous individuals revealed loss of β-sarcoglycan, the protein product of SGCB, and destabilization of the sarcoglycan complex. Although SGCB has been previously associated with limb-girdle muscular dystrophy, these homozygous individuals showed no biochemical or clinical signs of skeletal muscle involvement, indicating an absence of myopathy. Compared with variant-negative patients with DCM, homozygous individuals also had a higher risk of early-onset adverse cardiac events. Together, these findings identify c.243+6T>A in SGCB as a cause of isolated DCM associated with unfavorable clinical outcomes.

Authors

Fangfang Li, Haruki Shinomiya, Yuki Kuramoto, Koshiro Kanaoka, Yuji Sakahashi, Yasuki Ishihara, Hidetaka Kioka, Seiko Ide, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N. Motoike, Kengo Kinoshita, Kinuko Ohneda, Hidetoshi Sakurai, Takahiro Okumura, Yohei Miyashita, Kota Jojima, Hisakazu Kato, Ken Matsuoka, Kazuya Tanabe, Shunsuke Nishimura, Seiji Takashima, Yoshihiro Asano, Yasushi Sakata