HNRNPC-Related Neurodevelopmental Disorder
HNRNPC-RNDD was first described in 2023. While other members of the HNRNP gene family were already linked to neurodevelopmental differences, this research provides the evidence needed to recognize HNRNPC as part of the same group of conditions.
HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder
The American Journal of Human Genetics(2023)
View PDFThe Gene
HNRNPC is a gene on chromosome 14 that encodes for heterogeneous nuclear ribonucleoprotein C (hnRNPC). Every person has two copies of the HNRNPC gene, but someone with HNRNPC-RNDD only has one functional copy. When one copy is not working as expected, there may not be enough functional hnRNPC to support typical development. This is called haploinsufficiency.
hnRNPC helps the body read and process RNA — the instructions cells use to make proteins. Specifically, hnRNPC plays roles in:
The gene is expressed all over the body (ubiquitously), with especially high expression in the heart and brain.
Why It Matters for the Brain
hnRNPC 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 hnRNPC levels are too low, 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: hnRNPC doesn't cause problems on its own — but without enough of it, many other important developmental genes don't function properly.
Most HNRNPC variants occur de novo, meaning they are random and not from either parent. Despite different types of variants, the resulting symptoms were similar across families. This supports the idea that the levels of hnRNPC — not the specific type of variant — is what drives the condition.
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
Lower levels of hnRNPC protein
Individuals with the recurrent variant produced significantly less hnRNPC than typical. This reduced dosage appears to be the key issue.
Disrupted RNA splicing
Researchers identified a consistent pattern of mis-spliced genes — many of which are important for intellectual ability and brain development.
Effects on neuron growth and communication
In mouse and cell-based studies, neurons with too little hnRNPC showed stunted growth and simpler branching. Neurons with too much hnRNPC also performed poorly. This tells us that the brain relies on precisely balanced levels of the hnRNPC during development.
Impacts on early brain wiring
During brain development, neurons must migrate to the correct position. Research found that when hnRNPC levels were disrupted, this migration was slowed — supporting the idea that early brain formation is sensitive to hnRNPC changes.
Developmental Delay/Intellectual Disability
100%All HNRNPC-RNDD individuals have developmental delay/intellectual disability to date. This ranges from mild to moderate.
Speech
100%All HNRNPC-RNDD individuals have speech delay or problems. Some individuals are nonverbal while some are delayed until 2 to 3 years old. Multiple people have articulation issues.
Motor
Most individuals with HNRNPC-RNDD have motor delay. One individual who has a large exon 1-3 deletion did not have gross motor delay, but other individuals had delayed walking, with first steps being up to 2.5 years old. All individuals have delays in fine motor skills.
Structural Brain Anomalies
Most individuals with HNRNPC-RNDD have structural brain anomalies. These are quite variable.
- Abnormal ventricles (particularly large ventricles/ventriculomegaly)
- Absent cochlea (leading to hearing loss)
- Polymicrogyria
- Delayed myelination
- Cysts
- Thalamic volume loss
- Small sinuses
Muscles
50%+Over half of individuals with HNRNPC-RNDD have hypotonia (low muscle tone). A small number of individuals with variants that escape nonsense mediated decay have hypermobile joints.
Hand and Feet Differences
~60%About 60% of individuals with HNRNPC-RNDD have hand and/or feet differences.
- Fetal fingertip pads or prominent fingertip pads
- Small metacarpals (bones of the hand)
- Sandal gap between toes
- Metatarsus adductus (front of the foot turns inward)
- Clinodactyly (curved finger)
- Brachydactyly (short fingers)
- Short or small hands or feet
Behavioral Differences
Most individuals with HNRNPC-RNDD have behavioral differences. These include a happy demeanor, ADHD, autism spectrum disorder (ASD), and difficulty falling or staying asleep. Tics have also been reported.
Seizures
~25%About a quarter of individuals with HNRNPC-RNDD have seizures. Individuals with variants that escape nonsense mediated decay are more likely to have seizures.
Skeletal Differences
~33%About a third of individuals with HNRNPC-RNDD have skeletal differences. Individuals with variants that escape nonsense mediated decay are more likely to have skeletal differences.
- Vertebrae anomalies
- Thin ribs
- Abnormal number of ribs
- Pectus excavatum-carinatum
- Tibia anomalies
- Open anterior fontanelle
- Short neck
- Brachycephaly
- Microcephaly
- Macrocephaly
Eye and Vision Anomalies
~45%Almost half of individuals with HNRNPC-RNDD have eye and/or vision anomalies.
- Myopia (near-sightedness)
- Colobomatous microphthalmia
- Strabismus
Receiving an HNRNPC-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 child with HNRNPC-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.
- Now that the condition has been discovered and published, we are gaining a better understanding of how it affects patients.
- The underlying biology is becoming clearer, which is the foundation for future treatments.
- The disorder is caused by a predictable mechanism (reduced protein levels), which may make it easier for researchers to develop targeted therapies one day.
- Children often have a happy, social demeanor, which is an important and positive trait reported across families.
- Early support and therapies (speech, motor, behavioral, and educational strategies) can make a meaningful difference.
- Connect with other families through our Facebook groups. Speaking with parents who understand what you're going through can be invaluable.
Dr. Arjan Bouman
Researcher
Erasmus Medical Center, Rotterdam, Netherlands
Dr. Arjan Bouman practices at Erasmus Medical Center in Rotterdam, Netherlands. He and his team published the first cases of HNRNPC-RNDD.
Join Our Research
We are running a Natural History Study for HNRNPC-RNDD at the HNRNP Family Foundation. Your participation helps advance research and treatment development.
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