Loss-of-function variants in HIVEP2 are a cause of intellectual disability

Siddharth Srivastava, Hartmut Engels, Ina Schanze, Kirsten Cremer, Thomas Wieland, Moritz Menzel, Max Schubach, Saskia Biskup, Martina Krei, Sabine Endele, Tim M. Strom, Dagmar Wieczorek, Martin Zenker, Siddharth Gupta, Julie Cohen, Alexander M. Zink, SakkuBai Naidu

Research output: Research - peer-reviewArticle

Abstract

Intellectual disability (ID) affects 2-3% of the population. In the past, many genetic causes of ID remained unidentified due to its vast heterogeneity. Recently, whole exome sequencing (WES) studies have shown that de novo variants underlie a significant portion of sporadic cases of ID. Applying WES to patients with ID or global developmental delay at different centers, we identified three individuals with distinct de novo variants in HIVEP2 (human immunodeficiency virus type I enhancer binding protein), which belongs to a family of zinc-finger-containing transcriptional proteins involved in growth and development. Two of the variants were nonsense changes, and one was a 1 bp deletion resulting in a premature stop codon that was reported previously without clinical detail. In silico prediction programs suggest loss-of-function in the mutated allele leading to haploinsufficiency as a putative mechanism in all three individuals. All three patients presented with moderate-to-severe ID, minimal structural brain anomalies, hypotonia, and mild dysmorphic features. Growth parameters were in the normal range except for borderline microcephaly at birth in one patient. Two of the patients exhibited behavioral anomalies including hyperactivity and aggression. Published functional data suggest a neurodevelopmental role for HIVEP2, and several of the genes regulated by HIVEP2 are implicated in brain development, for example, SSTR-2, c-Myc, and genes of the NF-κB pathway. In addition, HIVEP2-knockout mice exhibit several working memory deficits, increased anxiety, and hyperactivity. On the basis of the genotype-phenotype correlation and existing functional data, we propose HIVEP2 as a causative ID gene.

LanguageEnglish (US)
Pages556-561
Number of pages6
JournalEuropean Journal of Human Genetics
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Intellectual Disability
Exome
Brain
Genes
Haploinsufficiency
Microcephaly
myc Genes
Muscle Hypotonia
Nonsense Codon
Zinc Fingers
Memory Disorders
Genetic Association Studies
Aggression
Growth and Development
Short-Term Memory
Knockout Mice
Computer Simulation
Carrier Proteins
Reference Values
Anxiety

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Srivastava, S., Engels, H., Schanze, I., Cremer, K., Wieland, T., Menzel, M., ... Naidu, S. (2016). Loss-of-function variants in HIVEP2 are a cause of intellectual disability. European Journal of Human Genetics, 24(4), 556-561. DOI: 10.1038/ejhg.2015.151

Loss-of-function variants in HIVEP2 are a cause of intellectual disability. / Srivastava, Siddharth; Engels, Hartmut; Schanze, Ina; Cremer, Kirsten; Wieland, Thomas; Menzel, Moritz; Schubach, Max; Biskup, Saskia; Krei, Martina; Endele, Sabine; Strom, Tim M.; Wieczorek, Dagmar; Zenker, Martin; Gupta, Siddharth; Cohen, Julie; Zink, Alexander M.; Naidu, SakkuBai.

In: European Journal of Human Genetics, Vol. 24, No. 4, 01.04.2016, p. 556-561.

Research output: Research - peer-reviewArticle

Srivastava, S, Engels, H, Schanze, I, Cremer, K, Wieland, T, Menzel, M, Schubach, M, Biskup, S, Krei, M, Endele, S, Strom, TM, Wieczorek, D, Zenker, M, Gupta, S, Cohen, J, Zink, AM & Naidu, S 2016, 'Loss-of-function variants in HIVEP2 are a cause of intellectual disability' European Journal of Human Genetics, vol 24, no. 4, pp. 556-561. DOI: 10.1038/ejhg.2015.151
Srivastava S, Engels H, Schanze I, Cremer K, Wieland T, Menzel M et al. Loss-of-function variants in HIVEP2 are a cause of intellectual disability. European Journal of Human Genetics. 2016 Apr 1;24(4):556-561. Available from, DOI: 10.1038/ejhg.2015.151
Srivastava, Siddharth ; Engels, Hartmut ; Schanze, Ina ; Cremer, Kirsten ; Wieland, Thomas ; Menzel, Moritz ; Schubach, Max ; Biskup, Saskia ; Krei, Martina ; Endele, Sabine ; Strom, Tim M. ; Wieczorek, Dagmar ; Zenker, Martin ; Gupta, Siddharth ; Cohen, Julie ; Zink, Alexander M. ; Naidu, SakkuBai. / Loss-of-function variants in HIVEP2 are a cause of intellectual disability. In: European Journal of Human Genetics. 2016 ; Vol. 24, No. 4. pp. 556-561
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