Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy
Year: 2022
Type: article
Abstract: Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.
Authors: Tamara T. Koopmann, Yalda Jamshidi, Mohammad Naghibi-Sistani, Heleen M. van der Klift, Hassan Birjandi, Zuhair Al-Hassnan, Abdullah Alwadai, Giovanni Zifarelli, Ehsan G. Karimiani, Sahar Sedighzadeh, Amir Bahreini, Nayereh Nouri, Merlene Peter, Kyoko Watanabe, Hermine A. van Duyvenvoorde, Claudia A. L. Ruivenkamp, Aalbertine K. K. Teunissen, Arend D. J. Ten Harkel, Sjoerd G. van Duinen, Monique C. Haak, Carlos E. Prada, Gijs W. E. Santen, Reza Maroofian
Institutions: Leiden University Medical Center, St George's, University of London, Mashhad University of Medical Sciences, King Faisal Specialist Hospital & Research Centre, Centogene (Germany), Shahid Chamran University of Ahvaz, University of Pittsburgh, Isfahan University of Medical Sciences, Lurie Children's Hospital, Willem-Alexander Kinderziekenhuis, Northwestern University, UCL Queen Square Institute of Neurology, University College London
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,380
OpenAlex ID: W4306377397