Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.
HNRNPA1
juvenile‐onset myopathy
rimmed vacuoles
stop‐loss variant
whole‐exome sequencing
Journal
Muscle & nerve
ISSN: 1097-4598
Titre abrégé: Muscle Nerve
Pays: United States
ID NLM: 7803146
Informations de publication
Date de publication:
28 Jul 2024
28 Jul 2024
Historique:
revised:
06
07
2024
received:
28
11
2023
accepted:
14
07
2024
medline:
29
7
2024
pubmed:
29
7
2024
entrez:
29
7
2024
Statut:
aheadofprint
Résumé
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. 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). 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. 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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHGRI NIH HHS
ID : R01HG009141
Pays : United States
Organisme : NEI NIH HHS
Pays : United States
Organisme : National Heart, Lung and Blood Institute
ID : UM1HG008900
Organisme : Sanofi Genzyme
Organisme : Ultragenyx
Organisme : LGMD2I Research Fund
Organisme : Samantha J. Brazzo Foundation
Organisme : LGMD2D Foundation
Organisme : Muscular Dystrophy UK
Organisme : Coalition to Cure Calpain 3
Organisme : Bernard F. and Alva B. Gimbel Foundation
Organisme : Kurt+Peter Foundation
Informations de copyright
© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.
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