Phenotypic Analysis of 452 Individuals with CACNA1A-Related Neurodevelopmental Disorders
Abstract number :
3.363
Submission category :
12. Genetics / 12A. Human Studies
Year :
2023
Submission ID :
1170
Source :
www.aesnet.org
Presentation date :
12/4/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Laina Lusk, MMSc CGC – Children's Hospital of Philadelphia
Alexis Karlin, MD – Children's Hospital of Philadelphia; Shridhar Parthasarathy, BA – Children's Hospital of Philadelphia; Olivia Wilmarth, MS – University of South Carolina School of Medicine; Sarah McKeown Ruggiero, MS CGC – Children's Hospital of Philadelphia; Kim Thalwitzer, MD – Children's Hospital of Philadelphia; Noor Ibrahim, MD – Children's Hospital of Philadelphia; Donna Schaare, BS – Clemson University; Alina Ivaniuk, MD – Cleveland Clinic; Julia Koh, BS – Boston Children’s Hospital; Esther Cha, BA – Northwestern University; Vikram Mukherjee, MBS – Children's Hospital of Philadelphia; Luigi Boccuto, MD – Clemson University; Dennis Lal, PhD – Cleveland Clinic; Annapurna Poduri, MD MPH – Boston Children’s Hospital; Alfred George, MD – Northwestern University; Pangkong Fox, PhD – CACNA1A Foundation Inc; Sunitha Malepati, JD – CACNA1A Foundation Inc; Lisa Manaster, MA – CACNA1A Foundation Inc; Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale: CACNA1A-related neurodevelopmental disorders comprise a broad spectrum of clinical phenotypes, ranging from developmental and epileptic encephalopathy (DEE) with severe hemiplegic migraine (HM) to relatively mild disorders that may involve developmental delay, medication-responsive epilepsy, ataxia, or mild HM. Prior attempts to delineate the phenotypes and genotypes of this disorder have focused on case reports or small cohorts, with often limited phenotypic descriptions or parent-reported features. Absence of clear genotype-phenotype correlations impedes prognosis and treatment-planning for newly diagnosed families and hinders delineation of disease natural history.
Methods: We harmonized clinical data from 452 individuals with CACNA1A-related conditions using the Human Phenotype Ontology (HPO) framework. Our cohort included 416 individuals described in the literature as well as 36 previously unreported individuals from the Children’s Hospital of Philadelphia, Boston Children’s Hospital, and Cleveland Clinic. All generated data will be shared for interactive exploration through an online resource (https://cacna1a-portal.broadinstitute.org).
Results: We retrieved 265 variants spanning the CACNA1A gene and 13,208 associated clinical annotations. Significant overlap was present among overall phenotypes; however, broad phenotypic categories including DEE, neurodevelopmental disorder, HM, epilepsy, and ataxia were evident. Compared with protein-truncating variants, individuals with missense variants had a greater likelihood of HM (OR = 19.6, p < 0.001) and focal epilepsy (OR = 7.78, p < 0.001). In addition, individuals with early onset epilepsy (< 24 months) were more likely to have global developmental delay
Genetics