Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: HNRNPA1

Green List (high evidence)

Comment on list classification: There are at least 7 unrelated individuals reported in literature with monoallelic variants in HNRNPA1 that presented with distal myopathy. Disease onset is either juvenile or in early adulthood. The affected individuals harboured stop-loss, missense, and frameshift variants, either de novo or shown to segregated with disease in an autosomal dominant manner. Other variants in this gene have been reported as causal for juvenile-onset ALS, multisystem proteinopathy, and distal hereditary motor neuropathy. There is currently little to no correlation between the location of the causative variant and the corresponding phenotype, and no precise understanding of the different disease mechanisms. Nonetheless, there is sufficient evidence for this gene-disease relationship. HNRNPA1 should be promoted to Green for Distal myopathies at the next GMS update.

Created: 31 Oct 2025, 9:35 a.m. | Last Modified: 31 Oct 2025, 9:35 a.m.

Panel Version: 5.19

PMID: 39072769 Turner et al. 2024,
Two unrelated individuals with unsolved juvenile-onset myopathy with monoallelic stop loss variants in HNRNPA1. Probands presented with similar onset of slowly progressive extremity and facial weakness in early adolescence, both had elevated CK.
K1440-01 - heterozygous for c.1119A>C p.(*373Tyrext*6) - not in gnomAD v4
MNOT002-01 - heterozygous for c.1118A>C p.(*373Serext*6) - not in gnomAD v4

PMID: 34291734 Beijer et al., 2021
Family A - de novo c.908-2A>G, (p.G304Nfs*3) - exon skipping resulting in a truncated protein. Polish male with an axonal motor-predominant neuropathy (onset at 15yo).
Family B - c.1018C>G, p.Pro340Ala - Moroccan female with slowly-progressive juvenile-onset ALS (onset around 20yo) - method: WES
Family C - c.1117T>G; p.*373Gluext*6 - myopathy with distal and facial onset and severe proximal and bulbar weakness upon progression; Dutch, mother and son affected; onset at 8-9yo - seq method: WGS.
Family D - 500bp deletion, p.G304Nfs*3 - Asian Indian female, onset at 22yo; distal myopathy, facial weakness; method: Trio WGS.
Family E - c.941A>T, p.Asp314Val - American male, with onset at 36 yo, affected mother; chronic myopathy with rimmed vacuoles, diagnosed with inclusion body myositis; seq method: WES.
Family F - c.1117T>C, p.*373Glnext*6 - seq method: unknown. Male Belgian patient diagnosed with distal myopathy of Welander or Nonaka type, onset at 12yo.

PMID: 34722876 Hackman et al., 2021
Large Finnish family with adult-onset autosomal dominant distal myopathy (8 individuals affected, onset at 32-45 yo). Hand weakness and stumbling on the feet were the first symptoms. Affected individuals het for a 160 bp deletion in exon 10 of HNRNPA1 (hg19: chr12:54677979-54678138) - aberrant transcript is predicted to result in the mutant protein p.Gly356Asnfs*4.

HNRNPA1 is associated with AD Amyotrophic lateral sclerosis 20, OMIM:615426, as well as provisionally linked to AD Myopathy, distal, 3, OMIM:610099 and Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3, OMIM:615424 (OMIM accessed 30th Oct 2025).
Sources: Other

Created: 30 Oct 2025, 4:06 p.m. | Last Modified: 30 Oct 2025, 4:10 p.m.

Panel Version: 5.17

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Myopathy, distal, 3 , OMIM:610099; distal myopathy, MONDO:0018949

Publications

• 34291734
• 34722876
• 35550112
• 39072769