The HNRNPR gene encodes a member of the spliceosome C complex, which functions in pre-mRNA processing and transport. Although the first HNRNPR variant was observed in a large epilepsy cohort in 2016 (PMID: 26795593), HNRNPR was first reported in relation to syndromic intellectual disability in 2019 by Duijkers et al. (PMID: 31079900). Overlapping clinical characteristics in 5 reported individuals included developmental delay/intellectual disability, microcephaly, seizures, facial dysmorphism, brachydactyly, and other congenital abnormalities. At least 6 variants have been reported in 9 probands, including 1 splice-site, 3 frameshift, 1 nonsense, and 1 missense variants (PMIDs: 26795593, 31079900, 33874999). Variants were de novo in all instances in which parental DNA was available. A frameshift and a missense variant were recurrent, identified in two and three unrelated probands, respectively. Other reported missense variants without functional characterization were of unclear pathogenicity and were not scored (PMID: 33874999).
Other members of the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family have been recently implicated in neurodevelopmental disorders (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) (PMID: 33874999), supporting this gene-disease relationship.
In summary, there is definitive evidence supporting the relationship between HNRNPR and syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 3, 2023 (SOP Version 9).
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