Submission Details

HNRNPH2 was first reported in relation to X-linked complex neurodevelopmental disorder in 2016 (Bain et al., PMID: 27545675). Disease-causing variants in the HNRNPH2 gene have been found to cause a disorder originally known as HNRNPH2-related intellectual disability syndrome, which is characterized by developmental delay/intellectual disability, speech and language difficulties, behavioral problems, and hypotonia. Most of the disease-causing variants are de novo, missense variants located within or near the nuclear localization sequence (NLS), a highly conserved region between amino acids 194 and 220 that is essential for interaction with nuclear transport receptors. Of note, five male patients with nonsense and frameshift variants have been reported. They display milder phenotypes including developmental delay/intellectual disability, autistic features, and/or psychiatric co-morbidities.

Fifteen variants (missense, nonsense, frameshift) that have been reported in fifteen probands, in four publications (PMIDs: 27545675, 30887513, 33728377, 34907471), are included in this curation. Due to the gene having a single coding exon, protein truncating variants (PTVs) are anticipated to escape nonsense mediated decay. Due to this, the default score for PTVs has been decreased to 1.0 for this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

This gene-disease relationship is also supported by mice models and functional assays in patients’ cells (PMIDs: 34907471, 37463454). These studies both showed aberrant splice patterns in patients’ cells (induced pluripotent stem cells and primary dermal fibroblasts) harboring missense variants. Additionally, knock-in mice bearing two distinct pathogenic NLS variants (P209L, R206W) in Hnrnph2 demonstrated a phenotypic spectrum highly similar to clinical features observed in human patients, including craniofacial abnormalities, impaired motor function, and increased susceptibility to audiogenic seizures; male mice also had reduced survival. In contrast, two independent Hnrnph2 knockout (KO) mice showed no detectable phenotypes.The mechanism of pathogenicity appears to be gain of function or dominant negative based on the mouse model (PMID: 37463454), but additional evidence is still required for a comprehensive understanding.

In summary, there is definitive evidence supporting the relationship between HNRNPH2 and X-linked complex neurodevelopmental disorder. This 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 Intellectual Disability and Autism GCEP on June 13th, 2024 (SOP Version 10).

HNRNPH2 was first reported in relation to X-linked complex neurodevelopmental disorder in 2016 (Bain et al., PMID: 27545675). Disease-causing variants in the HNRNPH2 gene have been found to cause a disorder originally known as HNRNPH2-related intellectual disability syndrome, which is characterized by developmental delay/intellectual disability, speech and language difficulties, behavioral problems, and hypotonia. Most of the disease-causing variants are de novo missense variants located within or near the nuclear localization sequence (NLS), a highly conserved region between amino acids 194 and 220 that is essential for interaction with nuclear transport receptors. Of note, five male patients with nonsense and frameshift variants have been reported. They display milder phenotypes including developmental delay/intellectual disability, autistic features, and/or psychiatric co-morbidities.

Fifteen variants (missense, nonsense, frameshift) that have been reported in 15 probands in four publications (PMIDs: 27545675, 30887513, 33728377, 34907471) are included in this curation. Due to the gene having a single coding exon, protein truncating variants (PTVs) are anticipated to escape nonsense mediated decay. Thus, the default score for PTVs was decreased to 1.0 for this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.

This gene-disease relationship is also supported by mouse models and functional assays in patient cells (PMIDs: 34907471, 37463454). These studies both showed aberrant splice patterns in patient cells (induced pluripotent stem cells and primary dermal fibroblasts) harboring missense variants. Additionally, knock-in mice bearing two distinct pathogenic NLS variants (P209L, R206W) in Hnrnph2 demonstrated a phenotypic spectrum highly similar to clinical features observed in human patients, including craniofacial abnormalities, impaired motor function, and increased susceptibility to audiogenic seizures; male mice also had reduced survival. In contrast, two independent Hnrnph2 knockout mice showed no detectable phenotypes. The mechanism of pathogenicity appears to be gain of function or dominant negative based on the mouse model (PMID: 37463454), but additional evidence is still required for a comprehensive understanding.

In summary, there is definitive evidence supporting the relationship between HNRNPH2 and X-linked complex neurodevelopmental disorder. This 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 Intellectual Disability and Autism Gene Curation Expert Panel on June 13, 2024 (SOP Version 10).