Familial Transmission and Phenotypic Heterogeneity in Germline GATOR1-Related Epilepsy: A Systematic Review and Meta-Analysis
- 1Capital Institute of Pediatrics, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100020, China
- 2Department of Neurology, Capital Center for Children’s Health, Capital Medical University, Capital Institute of Pediatrics, Beijing 100020, China
- 3Capital Institute of Pediatrics–Peking University Teaching Hospital, Capital Center for Children’s Health, Capital Medical University, Beijing 100020, China
Abstract
Incomplete penetrance and variable expressivity complicate interpretation of germline GATOR1 variants and individual-level phenotype prediction. We conducted a family-based systematic review and meta-analysis, reconstructing individual-level data from published pedigrees and reassessing variants using GATOR1-specific classification criteria. Sixty-three studies were included; 59 contributed 734 individuals heterozygous for germline pathogenic or likely pathogenic (P/LP) variants from 227 families. The pooled proportion of affected individuals was 65.7%. Recurrent variant status, variant consequence, DEPDC5 protein domain, transmitting-parent phenotype, and overall parental origin did not consistently distinguish affected from unaffected individuals, although paternal DEPDC5 transmission showed an exploratory association with higher disease expression (90.4% vs. 82.4%, p = 0.032). Among affected individuals, missense variants were associated with earlier seizure onset than loss-of-function (LoF) variants (0.67 vs. 4.50 years, p = 0.002). LoF variants in the DEPDC5 LassoA domain showed exploratory associations with cognitive impairment, MRI abnormalities, and epilepsy surgery (FDR-adjusted p ≤ 0.046). An expanded synthesis identified 14 published same-gene germline–somatic second-hit cases, of which 85.7% had focal cortical dysplasia (FCD) IIa; quantifiable somatic variant allele fractions (VAFs) for sequence-variant second hits were below 5% in all six single-region cases, whereas multiregion sampling in three cases showed spatial variation, including values below 1%. These findings suggest that disease expression and post-onset phenotype represent partly distinct aspects of clinical heterogeneity in GATOR1-related epilepsy.
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BibTeX
@article{li2026familial,
title = {{Familial Transmission and Phenotypic Heterogeneity in Germline GATOR1-Related Epilepsy: A Systematic Review and Meta-Analysis}},
author = {Lingxue Li and Yawen Bao and Lihan Huo and Xinna Ji and Qian Chen},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219773},
url = {https://www.mdpi.com/1422-0067/27/21/9773},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Familial Transmission and Phenotypic Heterogeneity in Germline GATOR1-Related Epilepsy: A Systematic Review and Meta-Analysis
AU - Lingxue Li
AU - Yawen Bao
AU - Lihan Huo
AU - Xinna Ji
AU - Qian Chen
PY - 2026
DA - 2026/10/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219773
UR - https://www.mdpi.com/1422-0067/27/21/9773
AB - Incomplete penetrance and variable expressivity complicate interpretation of germline GATOR1 variants and individual-level phenotype prediction. We conducted a family-based systematic review and meta-analysis, reconstructing individual-level data from published pedigrees and reassessing variants using GATOR1-specific classification criteria. Sixty-three studies were included; 59 contributed 734 individuals heterozygous for germline pathogenic or likely pathogenic (P/LP) variants from 227 families. The pooled proportion of affected individuals was 65.7%. Recurrent variant status, variant consequence, DEPDC5 protein domain, transmitting-parent phenotype, and overall parental origin did not consistently distinguish affected from unaffected individuals, although paternal DEPDC5 transmission showed an exploratory association with higher disease expression (90.4% vs. 82.4%, p = 0.032). Among affected individuals, missense variants were associated with earlier seizure onset than loss-of-function (LoF) variants (0.67 vs. 4.50 years, p = 0.002). LoF variants in the DEPDC5 LassoA domain showed exploratory associations with cognitive impairment, MRI abnormalities, and epilepsy surgery (FDR-adjusted p ≤ 0.046). An expanded synthesis identified 14 published same-gene germline–somatic second-hit cases, of which 85.7% had focal cortical dysplasia (FCD) IIa; quantifiable somatic variant allele fractions (VAFs) for sequence-variant second hits were below 5% in all six single-region cases, whereas multiregion sampling in three cases showed spatial variation, including values below 1%. These findings suggest that disease expression and post-onset phenotype represent partly distinct aspects of clinical heterogeneity in GATOR1-related epilepsy.
SN - 1422-0067
ER -