DEPDC5 Mutations and Epilepsy: Improving the Understanding of Gene Penetrance
Abstract number :
3.375
Submission category :
12. Genetics / 12A. Human Studies
Year :
2022
Submission ID :
2204833
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Elizabeth Butler, PA-C – Cleveland Clinic; Costin Leu, PhD – Genomic Medicine Institute – Cleveland Clinic; Imad Najm, MD – Charles Shor Epilepsy Center – Cleveland Clinic; Dennis Lal, PhD – Genomic Medicine Institute – Cleveland Clinic
Rationale: Family studies have provided strong evidence for an incomplete penetrance of pathogenic DEPDC5 variants leading to epilepsy presenting with different seizure syndromes With more recent studies showing individuals who have a somatic loss-of-heterozygosity event, in addition to the germline variant, will develop focal cortical dysplasia. The aim of our study was to analyze all to date reported families with DEPDC5-related epilepsy, provide an updated average penetrance estimate, and assess whether penetrance rates depend on the variant type or any other available clinical information.
Methods: We performed a systematic literature review to identify publications on DEPDC5 variants to analyze the largest compilation of families to date with DEPDC5-related epilepsies. We utilized genotype and phenotype information available in the publications to estimate variant penetrance.
Results: In total, 53 out of 96 unique families met our study inclusion criteria and were used for analyses. The average penetrance in the combined cohort of 327 DEPDC5 variant carriers across all families was 67.3% (95% confidence interval = 0.62-0.72). While there were significantly more carriers with protein-truncating variants (PTV; 74%) than missense variants, the penetrance rates of the two variant types were statistically not different (PTV: 66.4% vs. missense: 69.8%; P=0.59). The average penetrance rates were also not different in males compared to females (P=0.62). By the time of the conference we also intend to further investigate penetrance as it relates to seizure onset zone, dysplasia, and non-epilepsy clinical phenotypes.
Conclusions: While variable penetrance rates of epilepsy-causing DEPDC5 variants have been reported, this comprehensive literature review refines the findings of previous studies. Further, we provide the first evidence that PTV and missense DEPDC5 variants have similar penetrance rates. The results of this study can help inform clinicians and genetic counselors when advising individuals and families with DEPDC5 variants on prognosis and family planning.
Funding: Not applicable
Genetics