HNRNPH1-Related Neurodevelopmental Disorder
HNRNPH1-RNDD was first described in 2018. While at first considered a type of Bain type intellectual disability (due to variants in the HNRNPH2 gene), a later publication highlighted that there are enough differences for HNRNPH1-RNDD to be an independent syndrome. There are likely undiagnosed individuals who have not been tested or were tested prior to the disorder's publication.
The Gene
HNRNPH1 is a gene that carries instructions for making a protein involved in RNA splicing – the way cells "edit" RNA messages before turning them into proteins. It is very closely related to the HNRNPH2 gene, both of which help control how brain cells grow, connect, and communicate. HNRNPH1 is located on chromosome 5, which is an autosome (not a sex chromosome), meaning changes in this gene can affect both boys and girls equally.
Why It Matters for the Brain
HNRNPH1 and HNRNPH2 are paralogues – genes that arose from a shared ancestor and now sit on different chromosomes but still perform very similar jobs. Both proteins help control alternative splicing in neurons and share an almost identical region that acts as a nuclear localization signal – a sort of "postal code" that tells the protein to go into the nucleus. When this signal is disrupted by a mutation, the protein cannot reach its correct location, which can disrupt brain development. The key difference: HNRNPH2 is on the X chromosome and mainly affects females, while HNRNPH1 is on chromosome 5 and can affect both boys and girls. HNRNPH1 can also have loss-of-function variants while HNRNPH2 cannot.
All HNRNPH1 variants to date have been de novo, meaning they do not occur in either parent. Multiple variant types have been observed.
Variant types observed:
- Missense variants — these may disrupt how the HNRNPH1 protein works. Some missense variants in the nuclear localization signal (NLS) prevent the protein from entering the nucleus where it performs its work.
- Frameshift and nonsense variants — these likely result in a shorter protein and/or loss of function.
- Indels (insertions and deletions) — removing small regions of the protein.
- Large duplications of exons — these may result in shorter protein, loss of function, or extra protein product.
Disrupted nuclear localization
Some HNRNPH1 variants affect the nuclear localization signal (NLS) – a region that tells the protein where to go inside the cell. When this signal is disrupted, HNRNPH1 cannot properly enter the nucleus to do its job of regulating RNA splicing.
Similarity to HNRNPH2
HNRNPH1 and HNRNPH2 are paralogues that share an almost identical protein sequence, including the nuclear localization signal. Disease-causing variants in this same location of HNRNPH2 cause HNRNPH2-RNDD, supporting the idea that HNRNPH1 variants cause a closely related but distinct disorder.
Developmental Delay/Intellectual Disability
100%All HNRNPH1-RNDD individuals have developmental delay/intellectual disability to date. This ranges from moderate to severe.
Motor
90%+Over 90% of individuals with HNRNPH1-RNDD have motor delay. Some individuals are non-ambulatory while others have significant delays.
Speech
~85%Most HNRNPH1-RNDD individuals have speech delay or problems. Some individuals are nonverbal while some are delayed.
Muscles
73%73% of individuals with HNRNPH1-RNDD have hypotonia (low muscle tone). 40% of individuals with HNRNPH1-RNDD have joint hypermobility.
Behavioral Differences
~75%About three quarters of individuals with HNRNPH1-RNDD have behavioral differences. These include autism spectrum disorder (ASD), one individual with schizophrenia, self-injurious behaviors, and anxiety.
Structural Brain Anomalies
~70%Most individuals with HNRNPH1-RNDD have structural brain anomalies. These are quite variable.
- Abnormal ventricles
- Cerebellar atrophy
- Abnormal corpus callosum
- Delayed myelination
- Cerebellar vermis hypoplasia
Eye and Vision Anomalies
~65%Most individuals with HNRNPH1-RNDD have eye and/or vision anomalies.
Skeletal Differences
~60%About 60% of individuals with HNRNPH1-RNDD have skeletal differences.
- Chest deformities
- Narrowing of disc bones
- Vertebrae anomalies
- Scoliosis
- Microcephaly
Growth
~55%Over half of individuals with HNRNPH1-RNDD have growth delay resulting in short stature. Several individuals have been dependent on g-tubes for feeding.
Seizures
~45%About 45% of individuals with HNRNPH1-RNDD have seizures.
Hand and Feet Differences
~40%About 40% of individuals with HNRNPH1-RNDD have hand and/or feet differences.
- Clubbed fingers and toes
- Sandal gap
- Long fingers
- Fetal fingertip pads
- Camptodactyly
- Clinodactyly
Physical Differences
Most individuals with HNRNPH1-RNDD have different facial features, although they are variable. Other physical differences have also been observed.
- Variable facial features
- Kidney anomalies
- Hypospadias (in males)
- Digestive issues such as constipation and GERD (~40%)
Receiving an HNRNPH1-RNDD diagnosis can feel overwhelming, but you are not alone. While this is a rare condition, our community is here to support you. Every child with HNRNPH1-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 recognized genetic cause, ending the diagnostic odyssey for families.
- HNRNPH1 is part of a larger HNRNP gene family already known to affect brain development, which strengthens the biological understanding.
- The clinical presentation shares features with HNRNPH2-related disorder, so insights from that community may be helpful.
- Children can benefit from early, proactive therapies including physical therapy, occupational therapy, speech therapy, feeding support, and orthopedic care.
- Gastrointestinal care may be important given the feeding difficulties and reflux observed in many individuals.
- Families can connect with others through the HNRNP Family Foundation and rare disease networks to share knowledge and support.
Sara Reichert
Licensed Genetic Counselor
Children's Hospital of Philadelphia, Philadelphia, PA, USA
Rafal Ploski
Head of Medical Genetics Department
Medical University of Warsaw, Warsaw, Poland
Join Our Research
We are running a Natural History Study for HNRNPH1-RNDD at the HNRNP Family Foundation. Your participation helps advance research and treatment development.
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