HNRNPDL

Inheritance Pattern: AD

Disease ID:MONDO:0012193

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0012193

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012193

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012193

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0015151

Submitter: ClinGen

*HNRNPDL* belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins and encodes the protein heterogeneous nuclear ribonucleoprotein D like. Ribonucleoproteins bind to pre-mRNA and are involved in splicing and nuclear export. The *HNRNPDL* gene contains nine exons and eight introns, and three isoforms are produced by alternate splicing. The domain content of these isoforms differs, and they show distinct subcellular localization and properties relating to solubility, propensity to aggregation, and phase separation (PMID: 31995753). Isoform 2, which is prone to aggregation due to the loss of the N-terminal intrinsically disordered region (IDR) but retention of the C-terminal IDR, or prion-like domain, is most highly expressed in tissues. *HNRNPDL* was first reported in relation to autosomal dominant limb girdle muscular dystrophy (LGMD; includes LGMD1G/LGMDD3) in 2014 (Vieira et al, PMID: 24647604), although linkage analysis implicated the locus in 2004 (PMID: 15367920). Features observed in patients include adult onset (2nd-6th decade) of progressive, predominantly proximal muscle weakness that subsequently involves the upper limbs. Limitation of finger and toe flexion, scapular winging, distal muscle weakness, muscle atrophy, respiratory muscle involvement, cataract, and neurogenic changes may also be present. Muscle biopsy shows variable signs of myopathy, including degeneration, fiber size variation, necrotic fibers, and rimmed vacuoles. Evidence supporting this gene-disease relationship includes case level, segregation, and experimental data. Three variants, all missense, reported in 10 probands from six publications and two abstracts are included in this curation (PMID: 24647604, 30604053, 31267206, 32407983, 32904822, 38982518; https://doi.org/10.1016/j.nmd.2023.07.197, https://doi.org/10.1016/j.nmd.2023.07.196). The two patients reported in abstracts could not be entered into the GCI but were awarded 1.0 and 0.1 pt, for a total of 9.1 points for variant-level data. In all but one patient, one of two recurrent missense changes at the same amino acid residue was identified, with three patients having p.(Asp378Asn) and six having p.(Asp378His). Functional studies have shown that these variants result in increased aggregation kinetics but disrupted fibrillation, reduced overall HNRNPDL protein expression but increased insolubility, and increased propensity for the protein to form stress granules (PMID: 31995753, 36646699; https://doi.org/10.1016/j.nmd.2023.07.197). The variant reported in the last patient, p.(Gly373Arg) (https://doi.org/10.1016/j.nmd.2023.07.196), was located nearby, consistent with a mutational hotspot. Given the limited number of variants reported, additional caution may be warranted when interpreting variants outside this region without functional support. Variants also segregated with disease in at least 24 additional affected family members (3 pts). The GCEP knows of two additional families with the p.(Asp378His) variant who have not been published, but the maximum for genetic evidence (12 pts) has been reached. The GCEP is also aware of a homozygous variant in this gene being reported in association with a consistent phenotype (https://doi.org/10.1016/j.nmd.2023.07.197); this alternative inheritance pattern will be evaluated in the future as additional evidence accumulates. The mechanism of disease is not well understood but may involve toxic gain of function. As an RNA binding protein containing a prion-like domain, *HNRNPDL* shares a biochemical function with other genes associated with neuromuscular disease phenotypes, such as *TARDBP*, *FUS*, *TAF15*, *EWSR1*, *TIA1*, *MATR3*, *HNRNPA1*, and *HNRNPA2B1* (PMID: 32292882). In some of these genes, missense variants also affect Asp residues in the prion-like domain. Drosophila models expressing human WT or mutant (Asp378Asn or Asp378His) HNRNPDL isoform 2 in muscle show mild muscle degeneration and disorganization, recapitulating the myopathic features observed in patient skeletal muscle (PMID: 31995753). Morpholino-mediated knockdown in zebrafish has also been reported to result in disorganized muscle fibers (PMID: 24647604), but the GCEP opted not to score this model due to a mismatch with the proposed mechanism of disease and insufficient demonstration of specificity. In summary, there is definitive evidence to support the relationship between *HNRNPDL* and autosomal dominant limb girdle muscular dystrophy (12 pts genetic evidence + 1.5 pts experimental evidence, for a total of 13.5 pts). This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies (MDM) GCEP on January 14, 2025 (SOP Version 11). This gene-disease pair was originally evaluated by the MDM GCEP (formerly LGMD VCEP) in January 2020. Following re-evaluation, the classification was upgraded from Moderate to Definitive due to additional reported cases and re-evaluation of variant impact on gene function and existing experimental data.