Clinical, immunohistochemical, and genetic characterization of splice-altering biallelic DES variants: Therapeutic implications
Janelle Geist Hauserman,
Chamindra G. Laverty,
Sandra Donkervoort,
Ying Hu,
Sarah Silverstein,
Sarah B. Neuhaus,
Dimah Saade,
Gabrielle Vaughn,
Denise Malicki,
Rupleen Kaur,
Yuesheng Li,
Yan Luo,
Poching Liu,
Patrick Burr,
A. Reghan Foley,
Payam Mohassel,
Carsten G. Bönnemann
Affiliations
Janelle Geist Hauserman
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Corresponding author
Chamindra G. Laverty
University of California, San Diego, San Diego, CA, USA
Sandra Donkervoort
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Ying Hu
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Sarah Silverstein
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Sarah B. Neuhaus
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Dimah Saade
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Gabrielle Vaughn
University of California, San Diego, San Diego, CA, USA
Denise Malicki
University of California, San Diego, San Diego, CA, USA
Rupleen Kaur
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Yuesheng Li
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Yan Luo
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Poching Liu
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
Patrick Burr
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
A. Reghan Foley
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Payam Mohassel
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Carsten G. Bönnemann
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Corresponding author
Summary: Pathogenic variants in the DES gene clinically manifest as progressive skeletal muscle weakness, cardiomyopathy with associated severe arrhythmias, and respiratory insufficiency, and are collectively known as desminopathies. While most DES pathogenic variants act via a dominant mechanism, recessively acting variants have also been reported. Currently, there are no effective therapeutic interventions for desminopathies of any type. Here, we report an affected individual with rapidly progressive dilated cardiomyopathy, requiring heart transplantation at age 13 years, in the setting of childhood-onset skeletal muscle weakness. We identified biallelic DES variants (c.640-13 T>A and c.1288+1 G>A) and show aberrant DES gene splicing in the affected individual’s muscle. Through the generation of an inducible lentiviral system, we transdifferentiated fibroblast cultures derived from the affected individual into myoblasts and validated this system using RNA sequencing. We tested rationally designed, custom antisense oligonucleotides to screen for splice correction in these transdifferentiated cells and a functional minigene splicing assay. However, rather than correctly redirecting splicing, we found them to induce undesired exon skipping. Our results indicate that, while an individual precision-based molecular therapeutic approach to splice-altering pathogenic variants is promising, careful preclinical testing is imperative for each novel variant to test the feasibility of this type of approach for translation.
