HNRNPH1-Related Neurodevelopmental Disorder
HNRNPH1-RNDD was first described in 2018. The paper first describing the disorder is here.
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.
Clinical Features
Developmental Delay/Intellectual Disability
All HNRNPH1-RNDD individuals have developmental delay/intellectual disability to date. This ranges from moderate to severe.
Motor
90% individuals with HNRNPHH1-RNDD have motor delay. Some individuals are nonambulatory while some have significant delays.
Structural Brain Anomalies
Most individuals with HNRNPH1-RNDD have structural brain anomalies. These are quite variable. The following have been reported:
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Abnormal ventricles
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Cerebellar atrophy
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Abnormal corpus callosum
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Delayed myelination
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Cerebellar vermis hypoplasia
Muscles
80% of individuals with HNRNPH1-RNDD have hypotonia (low muscle tone).
Almost half of individuals with HNRNPH1-RNDD have joint hypermobility.
Hand and Feet Differences
About 40% of individuals with HNRNPH1-RNDD have hand and/or feet differences. Reported differences include:
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clubbed fingers and toes
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talipes valgus
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long fingers
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pes planus
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camptodactyly
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clinodactyly
Physical Differences
Most individuals with HNRNPH1-RNDD have different facial features, although they are variable.
Kidney anomalies have been observed. Males may have hypospadias.
Digestive issues, such as constipation and GERD, are seen in about 40% of individuals with HNRNPH1-RNDD.
Speech
Most HNRNPH1-RNDD individuals have speech delay or problems. Some individuals are nonverbal while some are delayed.
Behavioral Differences
Three quarters of individuals with HNRNPH1-RNDD have behavioral differences. These include autism spectrum disorder (ASD), one individual with schizophrenia, aggression, and anxiety.
Seizures
About 40% of individuals with HNRNPH1-RNDD have seizures.
Skeletal Differences
40% of individuals with HNRNPH1-RNDD have skeletal differences. Reported differences include:
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chest deformities
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narrowing of iliac bones
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vertebrae anomalies
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scoliosis
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microcephaly
Eye and Vision Anomalies
Most individuals with HNRNPH1-RNDD have eye and/or vision anomalies. These include:
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myopia (near-sightedness)
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astigmatism
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retinopathy
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retinal dystophy
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strabismus
Growth
Over half of individuals with HNRNPH1-RNDD have growth delay resulting in short stature. Several individuals have been dependent on g-tubes for feeding.
The Genetics of HNRNPH1-RNDD
Multiple variant types have been observed. These include:
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Large duplications 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 hnRNPH1 protein works. Some missense variants in the nuclear localization signal (NLS) don't allow the protein to go into the nucleus in the cell, where it performs much of its work.
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Frameshift and nonsense variants. These likely result in a shorter protein and/or loss of function.
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Indels (insertions and deletions) removing small regions of the protein.
Above are some of the known variants in HNRNPH1.
We are still learning about HNRNPH1-RNDD!
Join our upcoming natural history study! More information soon!