Candidate HNRNP-RNDDs
These genes are under active investigation for potential association with neurodevelopmental disorders but have not yet been officially established.
HNRNPD
HNRNPD-RNDD has over 20 individuals reported in the medical literature. To date, most patients have been identified through large cohort studies such as SPARK or the Deciphering Developmental Disorders (DDD) study. The HNRNP Family Foundation is working to publish a paper on this disorder. HNRNPD has also been implicated in 4q21 deletions and duplications, which are also associated with neurodevelopmental features.
Clinical Features:
- De novo variants
- Developmental delay and/or borderline intellectual disability
- Learning disabilities
- Motor and speech delays
- Behavioral differences, particularly autism spectrum disorder
- Abnormalities of movement (dystonia, tremor, poor coordination)
- Hand and feet differences (overlapping toes, clinodactyly, small hands/feet)
- Subtle dysmorphic facial features (most commonly abnormal ears)
HNRNPDL
~5 individuals with potentially damaging variants in HNRNPDL have been identified. We have an ongoing study focused on these individuals with University of Miami to further characterize this potential disorder. hnRNPDL is known to regulate HNRNPD.
PCBP1 (aka HNRNPE)
13 individuals with de novo variants in PCBP1 have been reported in a preprint (not yet peer reviewed) from CHU Nantes. All of these individuals have intellectual disability and many have autism spectrum disorder. Functional studies have shown neuronal changes using mice and differences in alternative splicing.
Clinical Features:
- De novo variants
- Intellectual disability
- Autism spectrum disorder
HNRNPL
A handful of individuals with HNRNPL variants have been identified.
Clinical Features:
- Developmental delay and/or intellectual disability
- Behavioral differences such as autism spectrum disorder
HNRNPUL1
~10 individuals with likely damaging variants in HNRNPUL1 have been reported. Thus far, all individuals have missense variants.
Clinical Features:
- Missense variants only (to date)
- Borderline to mild developmental delay and/or intellectual disability
- Behavioral differences such as autism spectrum disorder
- Cardiac findings in some individuals
HNRNPUL2
~30 individuals with HNRNPUL2-RNDD have been reported or identified by the HNRNP Family Foundation. We are working to publish these findings. Individuals with HNRNPUL2-RNDD tend to have de novo variants.
Clinical Features:
- De novo variants
- Growth delay
- Borderline to moderate developmental delay/intellectual disability
- Motor and speech delay
- Behavioral differences (autism spectrum disorder, ADHD, sleep disturbances)
- Inconsistent dysmorphic facial features
Think your family member has a novel HNRNP-RNDD?
If you or your family member has received genetic testing with a variant of uncertain significance in an hnRNP-encoding gene, it is plausible that it is causative. Contact Dr. Maddie Gillentine for further guidance.
Frequently Asked Questions
Understanding candidate genes and the research process
A candidate gene is a gene in which individuals with potentially damaging genetic variants and neurodevelopmental conditions have been identified, but there has not been an official disorder associated with the gene.
The HNRNP Family Foundation works with researchers and clinicians to identify any individuals with potentially damaging genetic variants in an HNRNP gene. Once a cohort has been established (the more the better, but we tend to use 3 patients as the minimum), we can collect natural history/clinical data on those individuals and assess if there are shared clinical features. This alone can be published and sufficient evidence to establish a gene-disease relationship. The gold standard is to also have "functional studies," which could include an animal or cellular model.
The variants reported in candidate genes are often reported as "research findings" or as findings not currently associated with disease. We also work with large sequencing companies like GeneDx and Baylor Genetics to identify any individuals with new variants. These are almost always reported as variants of uncertain significance. Once a disorder is established, these variants may be reclassified.