Expanding the phenotype of intellectual disability caused by HIVEP2 variants

Abstract

De novo pathogenic variants in the human immunodeficiency virus enhancer type I binding protein 2 (HIVEP2) gene, a large transcription factor predominantly expressed in the brain have previously been associated with intellectual disability (ID) and dysmorphic features in nine patients. We describe the phenotype and genotype of two additional patients with novel de novo pathogenic HIVEP2 variants, who have previously unreported features, including hyperphagia and Angelman-like features. Exome sequencing was utilized in the investigation of the patients who had previously incurred a rigorous genetic workup for their neurodevelopmental delay, and in whom no genetic cause had been detected. Information pertaining to phenotype and genotype for new patients was collated along with data from previous reports, showing that the phenotypic spectrum of patients with HIVEP2 variants is broader than first noted. Additional characteristics are: an increased body mass index;and features of Angelman-like syndromes including: ID, limited speech, post-natal microcephaly, and hypotonia. Dysmorphic features vary between patients. As yet, no clear association between the type of gene aberration and phenotype can be concluded. HIVEP2-related ID needs to be considered in the differential diagnosis of patients with Angelman-like phenotypes and hyperphagia, and whole-exome sequencing should be considered in the genetic diagnostic armamentarium for patients with ID of inconclusive etiology. K E Y W O R D SAngelman-like syndrome, exome sequencing, HIVEP2, hyperphagia, intellectual disability

Genetic Etiologies in Developmental and/or Epileptic Encephalopathy With Electrical Status Epilepticus During Sleep: Cohort Study

“…A heterozygous HIVEP2 variant was identified in case 15. The same nonsense variant had been reported (Goldsmith et al, 2019). The considerable global developmental delay became apparent at the age of 2 years.…”

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum

“…heterogeneity in AS-like patients and expanding the differential diagnosis. Likewise, other studies have recently described new genes associated with Angelman-like phenotypes such as HIVEP2 [55] or UNC80 [56]. TBL1XR1, SATB2, SMARCE1 and ASXL3 are known transcriptional regulators acting through chromatin modification [46,57,58].…”

CircHivep2 contributes to microglia activation and inflammation via miR‐181a‐5p/SOCS2 signalling in mice with kainic acid‐induced epileptic seizures

“…There is an increased interest in the use of miRNAs to achieve this objective. 48 24,27,28 The next step in our research was to establish the interactions and pathways associated with circHiveP2. We found through online queries that circHivep2 could interact with miR-181a-5p and verified this with a dual-luciferase reporter assay.…”

“…[23][24][25] HIVEP2 has been associated with numerous regulatory pathways, including cMyc and NF-κB, 26,27 and is involved in cellular immunity and development processes. 25,28 Therefore, in the present study, we have identified the circRNA that are differentially expressed in a KA-induced model of SE in mice and have further assessed CircHivep2 because it may play a pivotal role in the regulation of epileptic seizures. We have carried out expression differentiation experiments using CircHivep2 and identified its key interaction partners.…”