De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy

  1. Sajan, Samin A.
  2. Gradisch, Ralph ORCID logo
  3. Vogel, Florian D.
  4. Coffey, Alison ORCID logo
  5. Salyakina, Daria
  6. Soler, Diana
  7. Jayakar, Parul
  8. Jayakar, Anuj
  9. Bianconi, Simona E.
  10. Cooper, Annina H.
  11. Liu, Shuxi
  12. William, Nancy ORCID logo
  13. Benkel-Herrenbrück, Ira
  14. Maiwald, Robert
  15. Heller, Corina
  16. Biskup, Saskia
  17. Leiz, Steffen
  18. Westphal, Dominik Sebastian ORCID logo
  19. Wagner, Matias ORCID logo
  20. Clarke, Amy ORCID logo
  21. Stockner, Thomas
  22. Ernst, Margot
  23. Kesari, Akanchha
  24. Krenn, Martin ORCID logo

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1000 Titel
  • De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy
1000 Autor/in
  1. Sajan, Samin A. |
  2. Gradisch, Ralph |
  3. Vogel, Florian D. |
  4. Coffey, Alison |
  5. Salyakina, Daria |
  6. Soler, Diana |
  7. Jayakar, Parul |
  8. Jayakar, Anuj |
  9. Bianconi, Simona E. |
  10. Cooper, Annina H. |
  11. Liu, Shuxi |
  12. William, Nancy |
  13. Benkel-Herrenbrück, Ira |
  14. Maiwald, Robert |
  15. Heller, Corina |
  16. Biskup, Saskia |
  17. Leiz, Steffen |
  18. Westphal, Dominik Sebastian |
  19. Wagner, Matias |
  20. Clarke, Amy |
  21. Stockner, Thomas |
  22. Ernst, Margot |
  23. Kesari, Akanchha |
  24. Krenn, Martin |
1000 Verlag Springer International Publishing
1000 Erscheinungsjahr 2024
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2024-04-02
1000 Erschienen in
1000 Quellenangabe
  • 32(8):912-919
1000 Copyrightjahr
  • 2024
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41431-024-01600-3 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291759/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • <jats:title>Abstract</jats:title><jats:p>Nine out of 19 genes encoding GABA<jats:sub>A</jats:sub> receptor subunits have been linked to monogenic syndromes characterized by seizures and developmental disorders. Previously, we reported the de novo variant p.(Thr300Ile) in <jats:italic>GABRA4</jats:italic> in a patient with epilepsy and neurodevelopmental abnormalities. However, no new cases have been reported since then. Through an international collaboration, we collected molecular and phenotype data of individuals carrying de novo variants in <jats:italic>GABRA4</jats:italic>. Patients and their parents were investigated either by exome or genome sequencing, followed by targeted Sanger sequencing in some cases. All variants within the transmembrane domain, including the previously reported p.(Thr300Ile) variant, were characterized in silico and analyzed by molecular dynamics (MD) simulation studies. We identified three novel de novo missense variants in <jats:italic>GABRA4</jats:italic> (NM_000809.4): c.797 C &gt; T, p.(Pro266Leu), c.899 C &gt; A, p.(Thr300Asn), and c.634 G &gt; A, p.(Val212Ile). The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells. Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4). MD simulations of the three variants within the transmembrane domain of the receptor indicate that sub-microsecond scale dynamics differ between wild-type and mutated subunits. Taken together, our findings further corroborate an association between <jats:italic>GABRA4</jats:italic> and a neurological phenotype including variable neurodevelopmental, behavioral and epileptic abnormalities.</jats:p>
1000 Sacherschließung
lokal Adolescent [MeSH]
lokal Female [MeSH]
lokal Humans [MeSH]
lokal /631/208/514/2254
lokal /631/208/2489/144
lokal Mutation, Missense [MeSH]
lokal Receptors, GABA-A/genetics [MeSH]
lokal /631/208/366
lokal Article
lokal Male [MeSH]
lokal /45/77
lokal Developmental Disabilities/pathology [MeSH]
lokal Epilepsy/pathology [MeSH]
lokal /45/23
lokal Developmental Disabilities/genetics [MeSH]
lokal Phenotype [MeSH]
lokal Child [MeSH]
lokal Epilepsy/genetics [MeSH]
lokal article
lokal /631/378/1689/178
lokal Child, Preschool [MeSH]
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/U2FqYW4sIFNhbWluIEEu|https://orcid.org/0000-0002-3312-2472|https://frl.publisso.de/adhoc/uri/Vm9nZWwsIEZsb3JpYW4gRC4=|https://orcid.org/0000-0002-1338-8513|https://frl.publisso.de/adhoc/uri/U2FseWFraW5hLCBEYXJpYQ==|https://frl.publisso.de/adhoc/uri/U29sZXIsIERpYW5h|https://frl.publisso.de/adhoc/uri/SmF5YWthciwgUGFydWw=|https://frl.publisso.de/adhoc/uri/SmF5YWthciwgQW51ag==|https://frl.publisso.de/adhoc/uri/QmlhbmNvbmksIFNpbW9uYSBFLg==|https://frl.publisso.de/adhoc/uri/Q29vcGVyLCBBbm5pbmEgSC4=|https://frl.publisso.de/adhoc/uri/TGl1LCBTaHV4aQ==|https://orcid.org/0000-0002-7979-3634|https://frl.publisso.de/adhoc/uri/QmVua2VsLUhlcnJlbmJyw7xjaywgSXJh|https://frl.publisso.de/adhoc/uri/TWFpd2FsZCwgUm9iZXJ0|https://frl.publisso.de/adhoc/uri/SGVsbGVyLCBDb3JpbmE=|https://frl.publisso.de/adhoc/uri/Qmlza3VwLCBTYXNraWE=|https://frl.publisso.de/adhoc/uri/TGVpeiwgU3RlZmZlbg==|https://orcid.org/0000-0003-4870-9863|https://orcid.org/0000-0002-4454-8823|https://orcid.org/0009-0006-1319-1311|https://frl.publisso.de/adhoc/uri/U3RvY2tuZXIsIFRob21hcw==|https://frl.publisso.de/adhoc/uri/RXJuc3QsIE1hcmdvdA==|https://frl.publisso.de/adhoc/uri/S2VzYXJpLCBBa2FuY2hoYQ==|https://orcid.org/0000-0003-3026-3082
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1000 Erstellt am 2025-07-05T10:54:14.871+0200
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