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Human Genetics

, Volume 136, Issue 7, pp 821–834 | Cite as

Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability

  • Nuria C. Bramswig
  • Hermann-Josef Lüdecke
  • Fadi F. Hamdan
  • Janine Altmüller
  • Filippo Beleggia
  • Nursel H. Elcioglu
  • Catharine Freyer
  • Erica H. Gerkes
  • Yasemin Kendir Demirkol
  • Kelly G. Knupp
  • Alma Kuechler
  • Yun Li
  • Daniel H. Lowenstein
  • Jacques L. Michaud
  • Kristen Park
  • Alexander P.A. Stegmann
  • Hermine E. Veenstra-Knol
  • Thomas Wieland
  • Bernd Wollnik
  • Hartmut Engels
  • Tim M. Strom
  • Tjitske Kleefstra
  • Dagmar Wieczorek
Original Investigation

Abstract

Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA–protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.

Keywords

Intellectual Disability Intellectual Disability Microcephaly Missense Variant Facial Dysmorphisms 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We are grateful to the families for participating in this study and we thank Daniela Falkenstein and Sabine Kaya for excellent technical assistance. This work was in part supported by the German Ministry of Research and Education [Grant Numbers 01GS08164 (HE), 01GS08167 (DW), 01GS08163 (TMS), German Mental Retardation Network] as part of the National Genome Research Network. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998, Epi4K—Administrative Core NS077274, Epi4K—Sequencing, Biostatistics and Bioinformatics Core NS077303; Epi4K Project 1—Epileptic Encephalopathies NS077364, and Epi4K—Phenotyping and Clinical Informatics Core NS077276).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Nuria C. Bramswig
    • 1
  • Hermann-Josef Lüdecke
    • 1
    • 2
  • Fadi F. Hamdan
    • 3
  • Janine Altmüller
    • 4
  • Filippo Beleggia
    • 2
    • 5
  • Nursel H. Elcioglu
    • 6
    • 7
  • Catharine Freyer
    • 8
  • Erica H. Gerkes
    • 9
  • Yasemin Kendir Demirkol
    • 6
  • Kelly G. Knupp
    • 10
  • Alma Kuechler
    • 1
  • Yun Li
    • 11
  • Daniel H. Lowenstein
    • 8
  • Jacques L. Michaud
    • 3
    • 12
    • 13
  • Kristen Park
    • 10
  • Alexander P.A. Stegmann
    • 14
  • Hermine E. Veenstra-Knol
    • 9
  • Thomas Wieland
    • 15
    • 16
  • Bernd Wollnik
    • 11
  • Hartmut Engels
    • 17
  • Tim M. Strom
    • 15
    • 16
  • Tjitske Kleefstra
    • 18
  • Dagmar Wieczorek
    • 1
    • 2
  1. 1.Institut für HumangenetikUniversitätsklinikum Essen, Universität Duisburg-EssenEssenGermany
  2. 2.Institut für HumangenetikUniversitätsklinikum Düsseldorf, Heinrich-Heine-Universität DüsseldorfDüsseldorfGermany
  3. 3.CHU Sainte-Justine Research CenterMontrealCanada
  4. 4.Cologne Center for Genomics (CCG)University of CologneCologneGermany
  5. 5.Department I of Internal MedicineUniversity Hospital of CologneCologneGermany
  6. 6.Department of Pediatric GeneticsMarmara University Medical SchoolIstanbulTurkey
  7. 7.Eastern Mediterranean UniversityCyprusTurkey
  8. 8.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  9. 9.Department of GeneticsUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
  10. 10.Department of Pediatrics and NeurologyChildren’s Hospital Colorado, Anschutz Medical Campus, University of ColoradoAuroraUSA
  11. 11.Institute of Human GeneticsUniversity Medical Center GöttingenGöttingenGermany
  12. 12.Department of PediatricsUniversité de MontréalMontrealCanada
  13. 13.Department of NeurosciencesUniversité de MontréalMontrealCanada
  14. 14.Department of Clinical GeneticsMaastricht University Medical CenterMaastrichtThe Netherlands
  15. 15.Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
  16. 16.Institute of Human GeneticsTechnische Universität MünchenMunichGermany
  17. 17.Institute of Human GeneticsUniversity of BonnBonnGermany
  18. 18.Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands

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