Understanding Genetic Heterogeneity Through Recurrent Variants in STXBP1
Abstract number :
2.359
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
827
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Katie Rose Sullivan, MS, CGC – Children's Hospital of Philadelphia
Julie Xian, BS – Children's Hospital of Philadelphia; Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia; Kristin Cunningham, MS, OTR/L – Children's Hospital of Philadelphia; Samuel Pierce, PT, PhD, NCS – Children's Hospital of Philadelphia; Ben Prosser, Ph.D. – University of Pennsylvania; Michael Boland, Ph.D. – University of Pennsylvania; Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale: The phenotypic range of STXBP1-related disorders limits recognition of clear genotype-phenotype associations. Individuals with the same genetic variant in STXBP1 can have divergent clinical trajectories, while individuals with different variants in STXBP1 can have similar trajectories. Resolution of genetic variability is critical for precise prognostication and targeted therapeutic strategies.
Methods: Here, we assessed clinical presentations including epilepsy and developmental outcomes in 94 individuals with the three most common recurrent genetic variants in STXBP1: p.Arg406Cys/His (n=40), p.Arg292Cys/His/Leu/Pro (n=30), and p.Arg551Cys/Gly/His/Leu (n=24). We analyzed 3,705 derived phenotypic terms across the cohort, and 2,447 cumulative patient-months of epilepsy and developmental histories in a subset of individuals followed at a single pediatric healthcare network. Clinical trajectories and outcomes were stratified within recurrent variant hotspots; phenotypic signatures were analyzed between individual genetic variants occurring at the same locus versus clinical phenotypes in a broader cohort of 534 individuals with STXBP1-related disorders.
Results: Individuals with the recurrent variants p.Arg406Cys/His, p.Arg292Cys/His/Leu/Pro, and p.Arg551Cys/Gly/His/Leu account for up to 17.6% of individuals with STXBP1-related disorders. When assessing individuals with p.Arg406Cys (n=20) and p.Arg406His (n=20) variants, a higher risk of spastic tetraplegia was observed in individuals with p.Arg406His (Odds ratio (OR) 2.9), while a lower risk was associated with individuals with p.Arg406Cys (OR 1.2). In contrast, both individuals with p.Arg406Cys and p.Arg406His had an increased risk of bruxism (OR = 5.6). When comparing individuals with p.Arg292His (n=18) versus p.Arg292Cys (n=10) variants, the 3-fold increased risk for focal impaired awareness seizures observed when grouping variants together was primarily driven by individuals with p.Arg292Cys than when assessing p.Arg292His variants separately. Similarly, when analyzing p.Arg551Cys (n=18) and p.Arg551His (n=4) variants, the risk for generalized-onset seizure and developmental regression could both be localized to individuals with the p.Arg551Cys variant (OR 3.6, OR 3.5). A higher degree of phenotypic resemblance with individual variants was observed than with grouping the recurrent hotspots. Furthermore, when comparing epilepsy trajectories, we found high variability. Additionally, the distribution of Gross Motor Function Measure scores across individuals demonstrated a wide range of developmental outcomes.
Conclusions: We delineated phenotypic associations within and across individuals with recurrent variants in STXBP1 and demonstrated phenotypic signatures; precisely: spastic tetraplegia, bruxism, seizure types, and developmental regression, associated with specific recurrent variants in contrast to recurrent hotspots. Providing higher resolution to phenotypes associated with specific genetic etiologies will be critical in informing genotype-guided and precision medicine approaches.
Funding: Children's Hospital of Philadelphia; National Institute of Neurological Disorders and Stroke
Genetics