Novel dominant stop-loss variant in HNRNPA1 in a patient with juvenile-onset myopathy

Topic:

Pre-Clinical Research

Poster Number: 266

Author(s):

Christine Bruels, PhD, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Johnnie Turner, BS, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Audrey Daugherty, BS, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Elicia Estrella, MS, LCGC, Department of Neurology, Division of Genetics and Genomics, Boston Children's Hospital, Seth Stafki, MS, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Hannah Littel, BS, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Lynn Pais, MS, Center for Mendelian Genomics, Broad Institute of MIT, Vijay Ganesh, MD, PhD, Center for Mendelian Genomics, Broad Institute of MIT, Anne O'Donnell-Luria, MD, PhD, Center for Mendelian Genomics, Broad Institute of MIT, Safoora Syeda, MD, Division of Pediatric Neurology, Department of Pediatrics, U of FL, College of Medicine, Partha Ghosh, MD, Department of Neurology, Boston Children’s Hospital, Christina Pacak, PhD, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School, Louis Kunkel, PhD, Department of Neurology, Boston Children’s Hospita, Peter Kang, MD, Paul and Sheila Wellstone Muscular Dystrophy Center and Dept of Neurology, U of MN Medical School

Background: The role of HNRNPA1 in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and heredity inclusion body myopathy (hIBM), has been well established. Recent reports have expanded the phenotypic spectrum of HNRNPA1 variants to include myopathies without inclusion bodies. The inheritance patterns are typically dominant.
Objectives: To identify the genetic cause of disease in a family with juvenile onset myopathy.
Results: We enrolled a patient with juvenile onset of progressive muscle weakness in proximal and distal upper limbs and distal lower limbs. The proband exhibited mild facial weakness, elbow contractures, generalized muscle hypotrophy, mild respiratory dysfunction, and scapular winging. The proband was still ambulatory at age 22. A muscle biopsy showed no inclusion bodies. Whole exome sequencing identified a heterozygous stop loss variant in HNRNPA1 (NM_002136): c.963A>C; p.*321Tyrext*6. A likely de novo origin of the c.963 variant was confirmed by Sanger sequencing.
Conclusions: The HNRNPA1 variant in this family is in the same codon as that reported by Beijer et al (2021) (c.961T>G; p.*321Gluext*6). The two affected individuals with the heterozygous c.961T>G variant presented with symptoms very similar to those seen in our family; although the proband lost ambulation in her early 30’s her affected son was still ambulatory at age 13. The two variants affecting p.321* are predicted to result in a slightly longer protein. Beijer et al suggested that this extended protein is translated in their patient, potentially leading to abnormal stress granule dynamics, slowing stress granule disassembly, and enabling stress granule stabilizing interactions. Our findings provide further support for the potential pathogenicity of these dominant stop-loss variants.