Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation

Sarah Silverstein; Rotem Orbach; Safoora Syeda; A Reghan Foley; Svetlana Gorokhova; Katherine G Meilleur; Meganne E Leach; Prech Uapinyoying; Katherine R Chao; Sandra Donkervoort; Carsten G Bönnemann

doi:10.1016/j.xhgg.2024.100354

Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation

HGG Adv. 2024 Sep 23;6(1):100354. doi: 10.1016/j.xhgg.2024.100354. Online ahead of print.

Affiliations

¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Rutgers New Jersey School of Medicine, 185 S Orange Ave, Newark, NJ 07103, USA; Undiagnosed Diseases Program, National Human Genome Research Institute, National Institute of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
² Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
³ Aix Marseille University, INSERM, MMG, U 1251 Marseille, France; Department of Medical Genetics, Timone Children's Hospital, APHM, Marseille, France.
⁴ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Ionis Pharmaceuticals, Carlsbad CA, USA.
⁵ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Division of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA.
⁶ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Research Center for Genetic Medicine, Children's National Research Institute, Children's National Medical Center, Washington, DC 20010, USA.
⁷ Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, USA.
⁸ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].

PMID: 39318092
DOI: 10.1016/j.xhgg.2024.100354

Abstract

Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) and NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G) in NEB. Transcriptomic sequencing on affected individual muscles revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Affected individuals' MRI patterns of muscle involvement were compared with the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these affected individuals better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. Our report introduces disease pathogenesis and manifestation as a result of alteration of isoform distributions in muscle.

Published by Elsevier Inc.