To date, nearly 50 individuals with mutations and deletions in the HNRNPU gene have been described in the medical literature. The mutation arises de novo (new) in the genetic material contained within the sperm or egg, or very early on after fertilization. The gene has been identified from groups of individuals with intellectual disability, epilepsy, and structural brain abnormalities who had mutations and microdeletions at the end of the long arm of chromosome 1.[i]–[viii] Several genes in this region can cause neurodevelopmental problems, including HNRNPU. Each person carries two copies of the gene, and a heterozygous mutation affecting one allele (copy) of HNRNPU, is sufficient to produce pathology.
Nearly all of these individuals identified thus far with a mutation in the HNRNPU gene have intellectual disabilities and epilepsy. However, there are significant differences amongst affected individuals. Further studies have evaluated additional individuals with mutations in the HNRNPU gene, looking for similar characteristics to further understand the role of the gene and how individuals are affected.[ix]–[xi] Common characteristics among individuals with a HNRNPU mutation include structural abnormalities such as microcephaly (small head circumference) and small or absent corpus callosum, a structure which connects the two cerebral hemispheres. Patients have moderate to severe intellectual disability, with prominent impairments in speech. Some individuals with mutations in HNRNPU have cardiac (heart) or renal (kidney) abnormalities, though not all. Certain facial features are commonly found, such as prominent eyebrows, thin upper lip, prominent nasal bridge or bulbous nose. Some individuals may have aggressive behavior while others have a pleasant demeanor. Stereotypies such as hand flapping behavior occur in many affected individuals.
Epilepsy, a disorder in which a person has spontaneous and recurrent seizures, occurs in almost all patients with HNRNPU mutations. Seizures typically begin before age 5 years with most starting by age 1 and often initially occur in the setting of fever (ie febrile seizure).
[1]Allen HS et al (Epi4K Consortium, EpilepsyPhenome/Genome Project). De novo mutations in epilepticencephalopathies. Nature.2013 Sep 12;501(7466):217-21. (PMID:23934111, PMCID:PMC3773011, DOI:10.1038/nature12439)
[2]Ballif BC et al. High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44. Hum Genet.2012Jan;131(1):145-56. (PMID:21800092, DOI:10.1007/s00439-011-1073-y)
[3]CaliebeA et al. Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene. Eur J Med Genet. 2010Jul-Aug;53(4):179-85. (PMID:20382278, DOI:10.1016/j.ejmg.2010.04.001)
[4]Hamdan FF et al. De novo mutationsin moderate or severe intellectual disability.PLoS Genet. 2014Oct 30;10(10):e1004772. (PMID:25356899, PMCID:PMC4214635, DOI:10.1371/journal.pgen.1004772)
[5]Hill AD et al. A 2-Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome.Am J Med Genet A.2007 Aug 1;143A(15):1692-8. (PMID:17603806, DOI:10.1002/ajmg.a.31776)
[6]NagamaniSC et al. Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44.Eur J Hum Genet. 2012Feb;20(2):176-9. (PMID:21934713, PMCID:PMC3260920, DOI:10.1038/ejhg.2011.171)
[7]Thierry G et al. Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.Am J Med Genet A. 2012Jul;158A(7):1633-40. (PMID:22678713, DOI:10.1002/ajmg.a.35423)
[8]van Bon BW et al. Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis.J Med Genet. 2008Jun;45(6):346-54. (PMID:18178631, DOI:10.1136/jmg.2007.055830)
[9]Bramswig NC et al. Heterozygous HNRNPUvariants cause early onset epilepsy and severe intellectual disability. Hum Genet.2017 Jul;136(7):821-834. (PMID:28393272, DOI:10.1007/s00439-017-1795-6)
[10]Depienne C et al. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU. Hum Genet. 2017 Apr;136(4):463-479. (PMID:28283832, PMCID:PMC5360844, DOI:10.1007/s00439-017-1772-0)
[11]Yates TM et al. De novo mutations in HNRNPUresult in a neurodevelopmental syndrome. Am J Med Genet A. 2017 Nov;173(11):3003-3012. (PMID:28944577, DOI:10.1002/ajmg.a.38492)