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Peer-reviewedCC BY 4.0Clinical Genetics

Pathogenicity of NUSAP1 Variants Is Defined by NMD‐Escape: Evidence From Two Novel Cases and Systematic Population‐Based Variant Analysis

  • Maureen Jacob1
  • Susann Badmann1
  • Stefania Bigoni2
  • Maria Iascone3
  • Ilaria Vivaldi2
  • Katharina Mayerhanser1
  • Robert Kopajtich1,4
  • Holger Prokisch1,4
  • Cristina Forest5
  • Sebastian Eck1,4
  • Michael Zech1,4,6
  • Elisabeth Graf1
4 more authors
  • Matias Wagner1,4
  • Juliane Winkelmann1,4
  • Theresa Brunet1
  • Melanie Brugger1
6 affiliations
  1. 1Institute of Human Genetics, School of Medicine and Health, Technical University of Munich Munich Germany
  2. 2Medical Genetics Unit, Department of Mother and Child and Department of Medical Science Ferrara University Hospital and Ferrara University Ferrara Italy
  3. 3Laboratory of Medical Genetics, Papa Giovanni XXIII Hospital Bergamo Italy
  4. 4Institute of Neurogenomics, Helmholtz Zentrum München Munich Germany
  5. 5Department of Medical Sciences, Pediatric Section University Hospital of Ferrara Ferrara Italy
  6. 6Institute for Advanced Study, Technical University of Munich Garching Germany
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Abstract

Protein‐truncating variants in the 3′ region of a transcript, evading mRNA degradation and giving rise to aberrant truncated proteins, are an underrecognized cause in Mendelian diseases. Here, we report two individuals with heterozygous de novo nonsense variants in the penultimate and last exon of NUSAP1, both presenting with early‐onset refractory epilepsy, global developmental delay, congenital microcephaly, and a recognizable facial gestalt. RNA sequencing performed in one individual did not show a reduction in expression, compatible with escape of aberrant transcripts from nonsense mediated mRNA decay (NMD). We systematically analyzed gnomAD population data to delineate a critical region at the 3′ region of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls, while frameshift variants producing C‐terminal elongations appear tolerated. This position‐dependent model provides guidance for diagnostic variant interpretation.

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Cite

BibTeXRIS
BibTeX
@article{jacob2026pathogenicity,
  title = {{Pathogenicity of NUSAP1 Variants Is Defined by NMD‐Escape: Evidence From Two Novel Cases and Systematic Population‐Based Variant Analysis}},
  author = {Maureen Jacob and Susann Badmann and Stefania Bigoni and Maria Iascone and Ilaria Vivaldi and Katharina Mayerhanser and Robert Kopajtich and Holger Prokisch and Cristina Forest and Sebastian Eck and Michael Zech and Elisabeth Graf and Matias Wagner and Juliane Winkelmann and Theresa Brunet and Melanie Brugger},
  journal = {Clinical Genetics},
  year = {2026},
  month = sep,
  doi = {10.1111/cge.70244},
  url = {https://doi.org/10.1111/cge.70244},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Pathogenicity of NUSAP1 Variants Is Defined by NMD‐Escape: Evidence From Two Novel Cases and Systematic Population‐Based Variant Analysis
AU  - Maureen Jacob
AU  - Susann Badmann
AU  - Stefania Bigoni
AU  - Maria Iascone
AU  - Ilaria Vivaldi
AU  - Katharina Mayerhanser
AU  - Robert Kopajtich
AU  - Holger Prokisch
AU  - Cristina Forest
AU  - Sebastian Eck
AU  - Michael Zech
AU  - Elisabeth Graf
AU  - Matias Wagner
AU  - Juliane Winkelmann
AU  - Theresa Brunet
AU  - Melanie Brugger
PY  - 2026
DA  - 2026/09/07
JO  - Clinical Genetics
DO  - 10.1111/cge.70244
UR  - https://doi.org/10.1111/cge.70244
AB  - Protein‐truncating variants in the 3′ region of a transcript, evading mRNA degradation and giving rise to aberrant truncated proteins, are an underrecognized cause in Mendelian diseases. Here, we report two individuals with heterozygous de novo nonsense variants in the penultimate and last exon of NUSAP1, both presenting with early‐onset refractory epilepsy, global developmental delay, congenital microcephaly, and a recognizable facial gestalt. RNA sequencing performed in one individual did not show a reduction in expression, compatible with escape of aberrant transcripts from nonsense mediated mRNA decay (NMD). We systematically analyzed gnomAD population data to delineate a critical region at the 3′ region of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls, while frameshift variants producing C‐terminal elongations appear tolerated. This position‐dependent model provides guidance for diagnostic variant interpretation.
SN  - 0009-9163
SN  - 1399-0004
ER  -