HNRNPH1 was first reported in relation to autosomal dominant syndromic intellectual disability in 2018 (Pilch et al., PMID: 29938792). The authors reported a male proband with a de novo p.Arg206Trp variant, which is analogous to the recurrent HNRNPH2 variant associated with HNRNPH2-related X-linked intellectual disability, Bain type. Affected individuals present with syndromic intellectual disability, dysmorphic facial features, absent or minimal verbal skills, brain abnormalities, ophthalmological abnormalities, genitourinary malformations, short stature, microcephaly, and hypotonia.
Eight de novo variants (4 missense, 1 in-frame deletion, 2 frameshift, and 1 splice) reported in ten probands in five publications (PMIDs: 23934111, 29938792, 32335897, 32685970, 33874999) are included in this curation. Four probands had missense variants affecting the Arg206 mutational hotspot within the nuclear localization signal, including three with p.Arg206Trp. Additional cases with HNRNPH1 de novo variants have been reported, but they were not included in this curation because individual phenotype information was not provided (PMIDs: 33057194, 33077954).
Pathogenic HNRNPH1 missense variants, particularly in the nuclear localization signal, may disrupt nuclear import and nucleic acid binding, leading to cytoplasmic accumulation and a possible toxic gain- or complex loss-of-function mechanism (PMIDs: 20308327, 40591994). Loss-of-function variants likely act through haploinsufficiency (PMIDs: 23934111, 32335897).
This gene-disease relationship is also supported by the biochemical function of HNRNPH1 and protein interaction. HNRNPH1 belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family, which regulates mRNA processing mechanisms, including RNA splicing; several genes in this family (HNRNPC, HNRNPD, HNRNPH2, HNRNPK, SYNCRIP [also known as HNRNPQ], HNRNPR, and HNRNPU) have been implicated in syndromic intellectual disability (PMID: 33874999).
In summary, there is definitive evidence supporting the relationship between HNRNPH1 and autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 16, 2024 (SOP Version 11).
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