Submission Details

hnRNPA2B1 was first reported in relation to autosomal dominant inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2) in 2013 (Kim HJ et al., PMID:23455423). IBMPFD2 families present with an incomplete penetrance of disabling muscle weakness in most cases, osteolytic bone lesions consistent with Paget disease in around half of cases, and frontotemporal dementia in a handful of cases. At least 5 variants, all missense, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.

Variants in hnRNPA2B1 have been reported in individuals with the following disease entities: amyotrophic lateral sclerosis, inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2) and oculopharyngeal muscular dystrophy 2. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism and inheritance pattern of amyotrophic lateral sclerosis and IBMPFD2. Therefore, the following disease entities have been lumped into one disease entity for this curation: amyotrophic lateral sclerosis (MONDO:0004976) and inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (OMIM:615422). The disease entity oculopharyngeal muscular dystrophy 2 (MONDO:0958195) has been split from this curation for difference in phenotype (especially ptosis and eye movement paralysis) and a distinct difference in molecular mechanism (frameshift variants that create the same novel amino acid series at the C-terminus of the protein).

Variants in this gene have been reported in at least 5 probands in 5 publications (PMID:37528043, 25617006, 25299611, 28389692, 23455423). Variants in this gene segregated with disease in 10 additional family members across 2 families.

This gene-disease relationship is supported by experimental evidence including biochemical function, protein interaction, functional alteration in both patient and non patient cells and a non-human model organism. Splicing sensitive microarrays showed that hnRNPA2B1 has intrinsic properties that make it particularly susceptible to relocalization within the cell that may result in splicing defects when under stress (PMID:22574288). Protein interaction with TDP-53 (TARDBP), which has been previously implicated in this disease, is demonstrated in the literature (PMID:16157593). Functional alteration consistent with the disease has been demonstrated in patient cells (PMID: 27773581, 23455423) and HeLa cells (PMID: 23455423). Finally, a supporting drosophila model exists but has not been scored at full points as it is not a particularly strong model for this human disease (PMID: 23455423).

This gene-disease pair was originally evaluated to have a limited gene-disease relationship by the Amyotrophic Lateral Sclerosis Spectrum Disorders Gene Curation Expert Panel on October 28, 2021. It was reevaluated on October 24, 2024. As a result of this reevaluation, the classification changed to a moderate gene-disease relationship. This classification change is due to a reevaluation of the lumping and splitting; the prior curation was completed with amyotrophic lateral sclerosis (MONDO:0004976) as the disease entity and in the re-curation the group has decided to lump amyotrophic lateral sclerosis and multisystem proteinopathy under the disease entity inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (MONDO:0014178). This lumping allowed both genetic and experimental evidence available at the time of the last curation, but excluded due to disease entity, to be scored. Since the original curation one more case has been added to the literature and is scored in this curation (PMID:37528043).

This classification was approved by the ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders Gene Curation Expert Panel on the meeting date October 24, 2024 (SOP Version 11).