HNRNPU-NDD, Detailing the Ultrarare Neurodevelopmental Disorder

HNRNPU-NDD is an ultrarare autosomal dominant neurodevelopmental disorder causing symptoms such as seizures and intellectual disabilities in a known >100 individuals worldwide.

Introduction

HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) is an ultrarare autosomal dominant disorder caused by a pathogenic variant in the HNRNPU gene.  Individuals with these variants can exhibit a wide range of symptoms, but most commonly experience seizures, intellectual disability, and developmental delay.  HNRNPU-NDD is a relatively newly discovered genetic disorder, with few people diagnosed since its discovery in 2010.  Currently, there is no cure for HNRNPU-NDD.  However, we are hopeful that with improved diagnostic protocols and further research, a targeted therapeutic may be developed.

Tell me about this rare disease.

Genetic basis: HNRNPU-NDD is an autosomal dominant disorder typically caused by a de novo, pathogenic variant in the HNRNPU gene [1] [2].  The HNRNPU gene, at locus 1q44, encodes a protein called heterogeneous nuclear ribonucleoprotein U (hnRNP U) [2].  It is the largest protein in the heterogeneous nuclear ribonucleoprotein (hnRNP) family and has diverse roles in DNA and RNA processing [3] [4] [5].  The HNRNPU protein is involved in alternative splicing, gene regulation, and chromatin organization, among other functions [3] [6] [7].  Mutations causing HNRNPU-NDD are most commonly thought to be loss-of-function, some being identified as missense, C-terminal truncation, splice site, and in-frame deletions, as seen below in Figure 1 [8].

Figure 1. Published variants in the HNRNPU transcript, as of 2022 [8].

Clinical Presentation:  People with HNRNPU-NDD experience a wide range of symptoms.  The most common symptoms exhibited by those with HNRNPU-NDD include moderate to severe intellectual disability (ID), developmental delay, speech delay, hypotonia, and seizures, which begin in early childhood [1] [9] [10].  Seizures typically begin in the form of early childhood febrile episodes, but later in life are commonly classified as tonic-clonic or absence seizures [1] [9].  Other less common symptoms recorded include behavioral issues, autistic features, vision impairments, cardiac abnormalities, sleep apnea, and feeding difficulties [1] [9].  Many people with a pathogenic HNRNPU variant also have dysmorphic facial features such as a prominent brow, long palpebral fissures, an overhanging columella, and a thin upper lip [1] [11] [12].    

Incidence:  HNRNPU-NDD is an ultra-rare disease, with just >100 affected individuals identified as of 2025 [9] [10].  Like many rare diseases, it is also likely an underdiagnosed disorder.

Brief history:

• 1992: Scaffold attachment factor A (SAF-A) protein identified in HeLa cells [13]

• 1994: SAF-A was identified at the same as the HNRNPU protein [14]

• 2010: HNRNPU-NDD was identified in a group of four patients with 1q44 microdeletions containing the HNRNPU gene [15] [16]

• 2022: 57 genetic variants causing HNRNPU-NDD identified [8]

• 2025: Several organizations worldwide are dedicated to funding research and treatment of HNRNPU [4] [17] [18].

The State of the Disorder Today:  Today, there is no cure for HNRNPU-NDD, leaving patients to try to treat the individual symptoms of the disorder.  The most common treatment for HNRNPU-NDD is the use of anti-seizure medications, which have been shown to ease epileptic symptoms [9].

What is it like to be a patient with this disease?

Who are the patients?  HNRNPU-NDD can affect people of all sexes and backgrounds [9].  However, with such a small population identified, it is unclear if lifespan is affected by this disorder.  Several adults with HNRNPU-NDD have been reported, but further research is needed to form a consensus on the progression and prognosis of the disorder [9] [10].

What do current treatment options look like?  Current treatment options involve managing the symptoms of the disorder.  Anti-seizure medications like sodium valproate have been effective in reducing seizures [9].  The ketogenic diet and/or a new generation of anti-seizure medications have been recommended to treat refractory seizures, however there is no single treatment option effective for all individuals [8] [9].  In addition to this, specialists in a wide range of fields can be consulted to cope with specific symptoms such as developmental delay and weight gain [19].  For the smaller population experiencing sleep apnea, supplemental oxygen can be utilized [9].

Are there advocacy groups?  Yes, there are several patient family-led advocacy groups.  Better Future 4 U (BF4U) is a global patient advocacy organization that provides support for patients and families affected by HNRNPU, in addition to fundraising for research and promoting awareness of the disorder [4].  The HNRNP Family Foundation is dedicated to advocating and also funding research for patients with neurodevelopmental disorders caused by genes in the HNRNP family [17] [20].  For example, The HNRNP Family Foundation has recently co-hosted both virtual and in-person conferences in New York City & Seattle. These meetings provide unique opportunities for caregivers, clinicians and scientists to come together for medical assessments, sample donations, and scientific talks to advance knowledge and stimulate collaborations for these rare disorders [3].  Around the world, there is also HNRNP Japan which is a patient and family advocate group for those affected by any disorder related to the HNRNP gene family [18].

Are there genetic tests?  Yes, due to the non-specific nature of clinical presentation in HNRNPU-NDD, a genetic test must be performed.  This test will likely be ordered after there are observable suggestive clinical findings such as developmental delay, ID, infant feeding difficulties, epilepsy, and/or other symptoms of HNRNPU-NDD [9].  Based on the variants that have been identified so far, Whole Exome Sequencing (WES) or whole genome sequencing (WGS) is likely to offer a diagnosis for HNRNPU-NDD [21]. 

How do scientists and clinicians study this disease?

Are there good/any model systems scientists can use to develop drugs?  Prof. Meena Balasubramanian from University of Sheffield and Sheffield Children’s NHS Foundation Trust is the international expert on HNRNPU-related disorder and published a large majority of the literature on this condition.  Her group has been building a HNRNPU-NDD cellular biorepository consisting of patient blood, skin-derived fibroblasts and induced pluripotent stem cells (iPSCs) and iPSC-derived neurons that are being characterized further [23].  Her group has also developed a methylation episignature for clarification of variants of uncertain significance (VUS) identified through the above genetic testing methods [22].  She has been working on developing a zebrafish model of the disorder (Prof. Meena Balasubramanian, e-mail communication, 2025).  In addition, she has an ongoing research program on developing AAV9 gene therapy vectors for HNRNPU-NDD [25].  Additionally, at the University of Sheffield, Elizabeth Seward is studying the electrophysiology of HNRNPU-NDD iPSC-derived neurons [23]. 

At Columbia University Irving Medical Center, Christopher Ricupero’s lab, with Dr. Barbara Corneo and Dr. Jennifer Bain are also building a HNRNP-RNDD cellular biorepository consisting of patient blood, skin-derived fibroblasts and induced pluripotent stem cells (iPSCs).  Dr. Ricupero suggests that these patient-derived cells will be useful human-based models for the HNRNPU-NDD research community and are planned for future neuronal disease/disorder modeling, biomarkers and as a cellular platform for therapeutic development [26].  Disease models of Hnrnpu-NDD mice have been previously developed to study the disorder at Columbia University Irving Medical Center’s Institute for Genomic Medicine.  A mouse model of Hnrnpu haploinsufficiency displays developmental delay and seizure susceptibility, similar to human HNRNPU-NDD patients [27].  Hnrnpu conditional knockout mice have also been developed, which have served to corroborate Hnrnpu’s critical role in brain development [6].  These mouse models are invaluable for learning about HNRNPU-NDD, but do not fully recapitulate the human disorder phenotype as no mouse model of HNRNPU-related disorders has spontaneous seizures like HNRNPU patients experience [28].

Figure 2: Brains of mice on postnatal day 8.  Top panel (H) is a wild-type Hnrnpu mouse brain and bottom panel (I) is a mouse brain with an Hnrnpu mutation that caused an underdeveloped brain lacking the telencephalon [6].

Have natural history studies been done?  Prof. Meena Balasubramanian from the University of Sheffield has published the largest patient cohort of HNRNPU-NDD to date and is conducting an ongoing natural history study focused on longitudinal clinical data and sample collection for HNRNPU [29].  Since 2018, Jennifer Bain and Columbia University have been recruiting and following patients with HNRNP-related disorders [30]. 

Certain physicians, scientists or centers that are experts?  Prof. Meena Balasubramanian from University of Sheffield translational lab has published extensively on HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD), runs the largest natural history study on the disorder, and is an advisor to Better Future 4 U, an HNRNPU patient advocacy organization [29] [9].  Dr. Stuart A. Wilson, also on the Better Future 4 U advisory board, is investigating the molecular mechanisms of the HNRNPU family of proteins at the University of Sheffield [31].  Dr. Christopher Ricupero is a neuroscientist from Columbia University and scientific advisory board member for Better Future 4 U, the HNRNP Family Foundation [3] [4].  Dr. Jennifer Bain and Dr. Barbara Corneo from Columbia University are also actively involved in research supporting the community of patients affected by mutations in the HNRNP gene family.  Dr. Maddie Gillentine is a Clinical Genomic Scientist at Baylor Genetics, research director for the HNRNP Family Foundation, and previously published on the gene family, HNRNP-Related Neurodevelopmental Disorders [20].  Dr. Orly Reiner at the Weizmann Institute has also contributed to HNRNPU-related research [6] [24].

What are the major challenges in studying and curing this disease?  More information is needed to fully understand the molecular link between HNRNPU and disease.  HNRNPU-NDD is difficult to study because of the diverse regulatory roles of hnRNP U and its impact on the expression of many different downstream genes [27].  Scientists have begun to elucidate these mechanisms by studying the transcriptome patterns in 2D cell lines as well as human brain organoid models of HNRNPU-related disorders [28] [32].  These models are imperfect as they do not mirror the complexity of the human disease; however, they further our understanding of HNRNPU biology, which is a step towards better understanding HNRNPU-NDD.  Additional human patient samples, human iPSC cell models, and better animal models will facilitate further research.

The Cure Corner: What is needed for a cure?

What are current therapies and treatments lacking?  No clinical guidelines have been established for treating HNRNPU-NDD, and there is no targeted treatment available.  Currently multidisciplinary care focused on managing the unique symptoms of the disorder is the most effective treatment.  For instance, utilizing different specialists, feeding therapy or gastronomy tube placement for those with feeding difficulties, and drugs such as anti-epileptic medications are often essential [19].  However, there is no single medication or treatment that works for all HNRNPU-NDD individuals [19].

Are there companies already developing drugs?  University of Sheffield is currently working on a gene therapy that will use a viral vector such as AAV-9 to deliver wild-type HNRNPU protein to treat haploinsufficiency of HNRNPU [23].  Prof. Meena Balasubramanian and Stuart Wilson from the University of Sheffield are also working on a targeted treatment through drug repurposing [33].  La Jolla Labs has collaborated with Columbia University and patient families to test the feasibility of an upregulation strategy for HNRNPU with antisense oligonucleotides (ASOs), but this work is still in development.

Could an RNA therapeutic fit the need?  At present, there are no FDA-approved RNA therapeutics targeting HNRNPU.  However, HNRNPU has been submitted to the n-Lorem Foundation queue [34].  Recently, advances in RNA technology have introduced a method called targeted augmentation of nuclear gene output (TANGO).  In this method, ASOs can be used to enhance the amount of normal protein produced from a non-mutated copy of a gene to produce more healthy protein (Figure 3) [6].  Whether the TANGO method could be therapeutically relevant for HNRNPU remains to be tested, but it would be a reasonable path to consider for this sort of disorder due to predicted haploinsufficiency.

Figure 3: Targeted augmentation of nuclear gene output (TANGO) can be implemented to increase healthy protein production in cases of haploinsufficiency [35].

Conclusion

Since HNRNPU-related neurodevelopmental disorder was only identified in 2010, there is still much to learn about it, both at the basic science level and clinically.  With just over 100 identified patients worldwide, it is likely that this rare disorder is undiagnosed [10].  It is our hope that with an increase in whole exome and whole genome sequencing, improved disease model development, and continued research on the link between HNRNPU and neurodevelopmental disorders, patients will see a rise in accurate diagnoses and improved likelihood for an RNA therapeutic treatment and other gene-directed therapies.  The HNRNPU community of scientists and advocates is active and engaged across the world, so the future is bright.

A very special thanks to Prof. Meena Balasubramanian, Dr. Christopher Ricupero, Melissa Keenan, and several HNRNPU-NDD patient families for taking the time to review our article prior to publication.

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