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Muscle and Nerve
Muscle and Nerve
Volume 70, Issue 4 Pages: 727-880 October 2024

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Johnnie Turner BS, Christine C. Bruels PhD, Audrey L. Daugherty BS, Elicia A. Estrella MS, CGC, Seth Stafki MS, CGC, Safoora B. Syeda MBBS, Hannah R. Littel BS, Lynn Pais MS, Vijay S. Ganesh MD, PhD, Hart G. W. Lidov MD, PhD, Simon M. L. Paine MD, Paul Maddison MD, Rachel E. Harrison BMBS, PhD, Volker Straub MD, PhD, Partha S. Ghosh MD, Christina A. Pacak PhD, Louis M. Kunkel PhD, Isabelle Draper PhD, Ana Topf PhD, Peter B. Kang MD

Introduction/Aims Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.

Methods Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES).

Results The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon.

Discussion Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.