{
  "abstract": "Background SYNGAP1-related developmental and epileptic encephalopathy (SYNGAP1-DEE) is generally considered a haploinsufficiency disorder, yet language development varies considerably between affected individuals. With targeted therapies, including antisense oligonucleotides (ASOs), approaching clinical evaluation, understanding genotype-specific differences is increasingly important. We investigated whether expressive language and functional communication are associated with SynGAP protein domains and variant class. Methods We analyzed cross-sectional caregiver-reported data linked to genetic reports from the international PATRE SYNGAP1 registry. Of 440 participants, 334 had variants that could be assigned to a protein domain and classified as missense (n=79) or truncating/splicing (n=255). Variants were mapped to seven predefined SynGAP protein regions. The primary outcome was a five-level current expressive language score. Secondary outcomes included acquisition of two-word phrases and CFCS-derived functional communication. Each domain was compared with all other regions within the same variant class using nonparametric tests and age-adjusted ordinal or logistic regression. Benjamini-Hochberg false discovery rate correction was applied. Results Missense variants in the C2 domain (aa248-392; n=28) were associated with markedly poorer expressive language (median score 1 vs. 2; age-adjusted OR 0.16, 95% CI 0.06-0.46; q=0.0025). Only 7.1% had acquired two-word phrases compared with 52.0% of individuals with missense variants outside C2 (OR 0.07; q=0.0023). Functional communication was also significantly impaired (OR 0.23, 95% CI 0.09-0.56; q=0.0052). Conversely, truncating/splicing variants in the PH domain (aa103-247; n=50) were associated with better expressive language (median 3 vs. 2; OR 3.52, 95% CI 1.99-6.24; q<0.001) and more frequent acquisition of two-word phrases (62.0% vs. 31.5%). No corresponding language association was observed for C2 truncating/splicing variants or for variants in the RasGAP domain. Conclusions Language outcomes in SYNGAP1-DEE are associated with both variant class and protein location. The marked impairment associated with C2 missense variants contrasts with the relatively preserved language abilities observed in PH truncating/splicing variants, suggesting that SYNGAP1-related disease cannot be fully explained by a uniform haploinsufficiency model alone. These findings support considering protein domain and variant class in future ASO trials, particularly for patient stratification, endpoint selection, and interpretation of treatment outcomes.",
  "abstract_shown": true,
  "affiliations": [
    "Paracelsus Medical University, EURAS Project, Salzburg, Austria"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "L. Kiwull"
    },
    {
      "name": "V. Schmeder"
    },
    {
      "name": "M. Zenker"
    },
    {
      "name": "M. Mengual Hinojosa"
    },
    {
      "name": "G. Kluger"
    },
    {
      "affs": [
        0
      ],
      "name": "K. Eschermann"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8me820frmy4k9.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.04.26367250",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367250v1.full",
  "id": "8me820frmy4k9",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367250v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367250v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8me820frmy4k9.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T12:20:48Z",
      "native_id": "10.64898/2026.11.04.26367250",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.11.04.26367250v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "Beyond Haploinsufficiency: Protein Domain and Variant Class Shape Language Outcomes in SYNGAP1-DEE",
  "title_text": "Beyond Haploinsufficiency: Protein Domain and Variant Class Shape Language Outcomes in SYNGAP1-DEE",
  "type": "preprint",
  "updated_at": "2026-11-07T00:20:54Z",
  "url": "https://research.draconitic.com/paper/8me820frmy4k9",
  "venue": "medRxiv",
  "versions": []
}