HNRNRPG (RBMX)-Related Neurodevelopmental Disorders
Two disorders have been described related to changes in the RBMX gene: Shashi-type intellectual disability and Gustavson syndrome, collectively termed RBMX-RNDDs. These disorders were described in 2015 and 2023, respectively. RBMX-RNDDs only occur in individuals with XY chromosomes (males).
The Gene
RBMX (RNA Binding Motif Protein, X-Linked), also known as HNRNPG, is a gene on chromosome X that encodes heterogeneous nuclear ribonucleoprotein G (hnRNPG). Individuals with two X chromosomes (referred to as females) have two copies of the RBMX gene, while those with XY chromosomes have only one copy. RBMX-RNDDs only occur in individuals with XY chromosomes. For individuals with RBMX-RNDDs, the protein that is made does not work as expected. RBMX helps the body read and process RNA — the instructions cells use to make proteins and keeps the genome stable. Specifically, RBMX plays roles in splicing, sister chromatid cohesion (important in cell division), genome stability through regulating the DNA damage response, and reading post-transcriptional modifications to RNA. The gene is expressed all over the body (ubiquitously), with especially high expression in the heart and brain.
Why It Matters for the Brain
hnRNPG helps control a process called alternative splicing — a mechanism cells use to "edit" RNA before making proteins. Think of this as cutting and assembling sentence fragments into different final messages. When hnRNPG does not work correctly due to too low of levels or other changes to the protein, this editing process can become inconsistent. Research found that the genes most affected by these disruptions are genes already known to be associated with intellectual disability and brain development. In other words: RBMX doesn't cause problems on its own — but without enough of it, many other important brain-development genes don't function properly.
Most RBMX variants are inherited from an unaffected mother or occur de novo, meaning they are random and not from either parent. Since it can be inherited from an unaffected mother to an affected son, some families have multiple generations of affected individuals with XY chromosomes (referred to as male). This X-linked recessive inheritance pattern means carrier females typically do not show symptoms.
Variant types observed:
- A recurring in-frame deletion seen in multiple unrelated individuals
- Frameshift variants expected to reduce the amount of functional protein
- Missense variants altering single amino acids
- A large deletion affecting multiple exons of the gene
Disrupted RNA Splicing
RBMX/hnRNPG helps control alternative splicing — the process of "editing" RNA before making proteins. When RBMX doesn't function properly, this editing process becomes inconsistent, affecting the production of many proteins important for development.
Genome Stability
RBMX plays a role in keeping the genome stable by regulating the DNA damage response. Disrupted RBMX function may affect how cells repair DNA damage.
Cell Division
RBMX is involved in sister chromatid cohesion, an important step in cell division. Problems with this process can affect how cells divide and replicate.
Impact on Brain Development Genes
Research has shown that the genes most affected by RBMX disruption are those already known to be associated with intellectual disability and brain development. RBMX acts as a regulator that, when absent, prevents many other critical genes from functioning properly.
Intellectual Disability
100%Intellectual disability has been observed in individuals with RBMX-RNDDs. The severity can vary depending on the specific variant and syndrome (Shashi-type ID or Gustavson syndrome).
Affects Males Only
RBMX-RNDDs only occur in individuals with XY chromosomes (males). Because the gene is on the X chromosome and males have only one X, they cannot compensate if their single copy has a variant.
Receiving an RBMX-RNDD diagnosis can feel overwhelming, but you are not alone. While this is an extremely rare condition, our community is here to support you. Every individual with RBMX-RNDD is unique, and the clinical features described here represent what has been observed across all known cases—your child may experience some, none, or different combinations of these features.
- There is now a clear genetic explanation, which can help with medical management, school planning, and access to services.
- The condition is X-linked recessive, meaning it primarily affects males. Carrier mothers are typically unaffected.
- Some families have multiple generations of affected males, as the variant can be inherited from an unaffected carrier mother.
- Research into RBMX and related genes continues to grow, bringing hope for better understanding and treatments.
- Connect with other families through the HNRNP Family Foundation community to share experiences and support.
Vandana Shashi, MD
Professor of Pediatrics
Duke University, Durham, NC, USA
Josefin Johansson
Researcher
MSc Medical Biology
Join Our Research
We are running a Natural History Study for HNRNPG-RNDD at the HNRNP Family Foundation. Your participation helps advance research and treatment development.
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