HNRNPC-Related Neurodevelopmental Disorder
HNRNPC-RNDD was first described in 2023. The paper describing the disorder is here.
Clinical Features
Developmental Delay/Intellectual Disability
All HNRNPC-RNDD individuals have developmental delay/intellectual disability to date. This ranges from mild to moderate.
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. The following have been reported:
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Abnormal ventricles, particulary large ventricles (ventriculomegaly)
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Absent cochlea (leading to hearing loss)
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Polymicrogyria
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Delayed myelination
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Cysts
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Thalamic volume loss
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Small sinuses
Muscles
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
About 60% of individuals with HNRNPC-RNDD have hand and/or feet differences. Reported differences include:
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fetal fingertip pads or prominent fingertip pads
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small metacarpals (bones of the hand)
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sandal gap between toes
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metatarsus adductus (front of the foot turns inward)
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clinodactyly (curved finger)
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brachydactyly (short fingers)
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short or small hands or feet
Hearing Loss
Almost half of individuals with HNRNPC-RNDD have eye and/or vision anomalies. These include:
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myopia (near-sightedness)
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colobomatous microphthalmia
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strabismus
Speech
All HNRNPC-RNDD individuals have speech delay or problems. Some individuals are nonverbal while some are delayed until 2-3 years old. Multiple people have articulation issues.
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
About a quarter of individuals with HNRNPC-RNDD have seizures. These have included:
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absence seizures
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generalized seizures
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epilepsy
Individuals with variants that escape nonsense mediated decay are more likely to have seizures.
Skeletal Differences
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. Reported differences include:
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vertebrae anomalies
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thin ribs
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abnormal number of ribs
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pectus excavatum-carinatum
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tiba anomalies
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open anterior fontanelle
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short neck
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brachycephaly
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microcephaly
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macrocephaly
Eye and Vision Anomalies
Almost half of individuals with HNRNPC-RNDD have eye and/or vision anomalies. These include:
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myopia (near-sightedness)
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colobomatous microphthalmia
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strabismus
The Genetics of HNRNPC-RNDD
Above are the two isoforms of hnRNPC at the protein level. Isoform 1 is at the top and isoform 2 is at the bottom. RRM: RNA Recognition Motif (important for RNA binding), bZLM (basic region zipper-like motif, CLZ: leucine-zipper like oligomerization domain, CTD: C-terminal domain. Variants are shown for each isoform. Also shown is the exact DNA change for the recurrent C-terminal deletions.
HNRNPC has two isoforms, or versions. These are called isoform 1 (NM_004500.4, top) and isoform 2 (NM_031314.3, bottom). Isoform 1 is expressed more than isoform 2.
Multiple variant types have been observed. These include:
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Large deletions of multiple exons. These may result a shorter protein and/or in loss of function. (light blue in diagram)
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Missense variants. These may disrupt how the hnRNPC protein works. (black in diagram)
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Frameshift variants. These likely result in a shorter protein and/or loss of function. (yellow in diagram)
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Small deletions of amino acids 284-292, resulting in a truncated protein. This exact variant has been seen in multiple patients.
The Scientists Working on HNRNPC
We are still learning about HNRNPC-RNDD!
Join our upcoming natural history study! More information soon!