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

Srivastava S, Engels H, Schanze I, Cremer K, Wieland T, Menzel M, Schubach M, Biskup S, Kreiss M, Endele S, Strom TM, Wieczorek D, Zenker M, Gupta S, Cohen J, Zink AM, Naidu S (2016)

Publication Type: Journal article

Publication year: 2016

Journal

European Journal of Human Genetics Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 24

Pages Range: 556-61

Journal Issue: 4

DOI: 10.1038/ejhg.2015.151

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-?B 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.

Authors with CRIS profile

Sabine Endele Institute of Human Genetics

Involved external institutions

Kennedy Krieger Institute US United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Universitätsklinikum Magdeburg A.ö.R. DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) CeGaT GmbH DE Germany (DE)

How to cite

APA:

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), 556-61. https://doi.org/10.1038/ejhg.2015.151

MLA:

Srivastava, Siddharth, et al. "Loss-of-function variants in HIVEP2 are a cause of intellectual disability." European Journal of Human Genetics 24.4 (2016): 556-61.

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