HNRNPU-Related Neurodevelopmental Disorder
HNRNPU-related neurodevelopmental disorder is a rare genetic condition that affects how a child grows, learns, and develops. It happens when one copy of the HNRNPU gene does not work as expected. Most children experience developmental delays, learning differences, and seizures that begin early in life. Even though symptoms can be significant, children often make progress over time, especially with supportive therapies and medical care. This condition is usually not inherited—in most families it occurs as a new, spontaneous genetic change.
Expanding the phenotype of HNRNPU-related neurodevelopmental disorder with emphasis on seizure phenotype and review of literature
American Journal of Medical Genetics Part A(2022)
View PDFClinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review
American Journal of Medical Genetics Part A(2020)
View PDFThe Gene
HNRNPU is a gene that helps control many important steps inside cells—especially in the brain. It's located on chromosome 1q44 and provides instructions for making a protein involved in organizing DNA, processing RNA messages, and regulating cell division. The protein is expressed throughout the body but is particularly important in the brain, with strong expression in the cerebellum.
Why It Matters for the Brain
When one copy of HNRNPU doesn't work properly, there isn't enough of the HNRNPU protein to support typical brain development. This is called haploinsufficiency. Because the brain depends heavily on this protein during development, changes in the gene can have wide-ranging effects on learning, movement, and other functions. The good news is that researchers are actively studying this gene, and gene therapy treatments are being explored as potential future treatments.
This condition is usually caused by a de novo variant—a new genetic change that happens spontaneously and is not inherited from either parent. This means the chance of it happening again in the same family is generally very low. The condition occurs when one copy of the gene doesn't work, leaving the body without enough HNRNPU protein (haploinsufficiency).
Variant types observed:
- Nonsense variants (early stop signals that cut the protein short)
- Frameshift variants (shift the reading frame of the gene)
- Splice site variants (affect how the gene is processed)
- Small insertions or deletions
- Large deletions (including chromosome 1q44 deletion syndrome)
Not enough protein
When one copy of the HNRNPU gene doesn't work, the body can't make enough of the HNRNPU protein. This is called haploinsufficiency—the single working copy just isn't enough to support typical development.
Brain development effects
HNRNPU is especially active in the developing brain and cerebellum. When protein levels are too low, it affects how brain cells grow, connect, and communicate with each other.
Learning & Development
97%Most children have developmental delays beginning in infancy. Learning differences can fall in the mild to severe range.
Speech & Communication
80%Many children have very limited speech or are nonverbal.
Seizures
95%Seizures occur in about 95% of children, often starting before age two. Many children respond to standard medications, but some may need a combination of treatments or dietary therapy like the ketogenic diet.
- Tonic-clonic seizures (stiffening and jerking) - most common
- Absence seizures (brief staring spells)
- Other types are less common but can occur
Muscle Tone & Movement
60%Babies often have low muscle tone (hypotonia), which can cause delays in sitting, crawling, or walking. Physical therapy helps improve strength and mobility.
Feeding & Growth
57%Feeding difficulties are common in infancy and early childhood due to low muscle tone and coordination challenges. Some children may need temporary or long-term feeding support, such as a feeding tube. Short stature may also be present.
Behavior & Personality
~63%Almost half of children meet criteria for autism spectrum disorder or have autistic-like features.
- Autistic features or autism diagnosis
- Attention challenges
- Self-stimulatory behaviors (like hand flapping)
Facial Features
97%Many children have mild facial differences, but these are not specific to the condition and are often subtle. No features are distinctive enough to diagnose HNRNPU-NDD by appearance alone.
- Prominent forehead
- Thin eyebrows
- Thin upper lip
- Widely spaced teeth
Heart Differences
30%Some children have heart differences, usually small septal defects (small holes between heart chambers). An echocardiogram is recommended after diagnosis to check for any heart concerns.
Eyes
36%About one third of children have eye issues, with strabismus (crossed eyes) being the most common. Regular eye exams are recommended.
Brain Imaging
~45%MRIs may show a range of differences, including enlarged ventricles or thinning of the corpus callosum. These findings help guide diagnosis but are not required—a normal MRI does not rule out this condition.
- Ventricular enlargement
- Thinning of the corpus callosum
- Delayed myelination
Other Possible Features
These features vary widely and do not appear in everyone. Regular monitoring by your medical team can help identify and address any concerns early.
- Kidney differences
- Undescended testes in boys (~20%)
- Hearing loss (rare)
- Sleep difficulties or breathing irregularities
- Joint looseness (hypermobility)
- Scoliosis or other skeletal findings (rare)
Receiving an HNRNPU-NDD diagnosis can feel overwhelming, but you are not alone. While this is a rare condition, our understanding has grown significantly since it was first described in 2013. Every child with HNRNPU-NDD is unique—the features described here represent what has been observed across all known cases, and your child may experience different combinations. Children often continue to make developmental progress throughout childhood, and families frequently describe their children as warm, affectionate, and resilient.
- Seizures occur in about 95% of children, often starting before age two, but many respond well to standard medications.
- Speech is typically the most affected skill—many children have very limited speech or are nonverbal, but communication devices (AAC) can help tremendously.
- Developmental delays are common, but early and ongoing therapies (physical, occupational, speech) make a meaningful difference.
- Many children show autistic traits, and behavioral therapies designed for autism can be very helpful.
- Babies often have low muscle tone (hypotonia), which improves with therapy and time.
- Families frequently describe their children as warm, affectionate, and resilient—this is an important positive trait.
- Life span does not appear to be significantly shortened, and adults with this condition have been reported.
- Gene therapy treatments for genetic forms of epilepsy, including HNRNPU-NDD, are currently being explored.
- Connect with other families through Simons Searchlight, the HNRNP Family Foundation, and our Facebook community.
Dr. Meena Balasubramanian
Clinical Geneticist & Researcher
Sheffield Children's Hospital, University of Sheffield, UK
Dr. Balasubramanian has published the largest cohort of individuals with HNRNPU-NDD and has gathered phenotypic data on more than 50 affected individuals. Her research focuses on genotype-phenotype correlation and establishing international registries to better understand the natural history of these conditions. She has also written the Unique patient support group information leaflet on the condition.
Join Our Research
We are running a Natural History Study for HNRNPU-RNDD at the HNRNP Family Foundation. Your participation helps advance research and treatment development.
HNRNP Caregiver Connect
Connect with caregivers across all HNRNP disorders
Publication List
View the latest research publications
Join our Natural History Study
Participate in research to help advance understanding
HNRNPU Facebook Group
Connect with other families affected by HNRNPU-RNDD
Simons Searchlight
Registry for rare genetic neurodevelopmental disorders including HNRNPU
GeneReviews Entry
Comprehensive medical resource for clinicians and families
Unique
Patient support group with information leaflet on HNRNPU-RNDD
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