Beyond Haploinsufficiency: Protein Domain and Variant Class Shape Language Outcomes in SYNGAP1-DEE
- 1Paracelsus Medical University, EURAS Project, Salzburg, Austria
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.
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BibTeX
@misc{kiwull2026beyond,
title = {{Beyond Haploinsufficiency: Protein Domain and Variant Class Shape Language Outcomes in SYNGAP1-DEE}},
author = {L. Kiwull and V. Schmeder and M. Zenker and M. Mengual Hinojosa and G. Kluger and K. Eschermann},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.26367250},
url = {https://www.medrxiv.org/content/10.64898/2026.11.04.26367250v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Beyond Haploinsufficiency: Protein Domain and Variant Class Shape Language Outcomes in SYNGAP1-DEE
AU - L. Kiwull
AU - V. Schmeder
AU - M. Zenker
AU - M. Mengual Hinojosa
AU - G. Kluger
AU - K. Eschermann
PY - 2026
DA - 2026/11/04
PB - medRxiv
DO - 10.64898/2026.11.04.26367250
UR - https://www.medrxiv.org/content/10.64898/2026.11.04.26367250v1
AB - 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.
ER -