Authors :
Presenting Author: Muhammed Cagri Bayraktutan, MD – Boston Children's Hospital
Abigail Sveden, MS, CGC – Boston Children's Hospital
Raymond Belanger Deloge, MS, CGC – Boston Children's Hospital
Jada Cameron, BS – Boston Children's Hospital
Jillian O'Toole, MS, GC – Boston Children's Hospital
Kellen Winden, MD, PhD – Boston Children's Hospital
Abby Donaghue, BS – Boston Children's Hospital
Celia Tam, PhD – Boston Children's Hospital
Ellen Hanson, PhD – Boston Children's Hospital
Maya Chopra, MBBS, FRACP – Boston Children's Hospital
Rationale:
ANKRD17 is an ankyrin repeat-containing protein implicated in cell cycle progression and neuronal differentiation. Heterozygous loss-of-function (LOF) variants in ANKRD17 cause Chopra-Amiel-Gordon syndrome (CAGS), a syndromic neurodevelopmental disorder with intellectual disability, speech delay, and dysmorphism (Chopra et al., Am J Hum Genet 2021;108:1138–1150). In the initial report of 34 individuals, epilepsy penetrance was 27%, with limited data on seizure severity and phenotypes. Through a longitudinal natural history study launched in 2022, we have deeply characterized 55 additional probands. Here, we report the genotypic spectrum, detailed epilepsy phenotypes, severity, and correlations with intellectual disability and autism spectrum disorder (ASD) in this unreported cohort.
Methods:
The study allows both remote and in-person participation, with three annual visits including medical history, review of genetic test reports, standardized neurobehavioral testing, and MRI review when available. In-person participants undergo a physical exam and optional EEG recordings. The Mann-Whitney U test was used for non-normally distributed independent group comparisons of developmental scores.
Results:
To date, 55 participants with pathogenic or likely pathogenic ANKRD17 variants have been enrolled, 42 with LOF (76%) and 13 with missense (23%). Epilepsy was confirmed in 24/55 (43%); in 21 (38%), it was the primary indication for genetic testing. Age at seizure onset ranged from neonatal to 15 years (mean 4.4). Among those with epilepsy, 13/24 (54%) experienced seizures less than once per year. Absence seizures were most frequent (13/24), followed by generalized tonic-clonic (11/24) and epileptic spasms (5/24); seven participants had multiple seizure types. Clinical EEGs showed ictal abnormalities in nine and interictal abnormalities in seven. Brain imaging revealed findings consistent with ictal semiology in six and unrelated abnormalities in three. Ten achieved seizure control with a single antiseizure medication, while five met criteria for drug-resistant epilepsy. Epilepsy was the primary concern for two families.
Compared to participants without epilepsy, we observed a trend (not statistically significant) toward lower Vineland Adaptive Behavior Scales (VABS) and Kaufman Brief Intelligence Test (KBIT) scores in the epilepsy group. Median VABS adaptive behavior composite score was 63 (range 22-86) in the epilepsy group, and 69 (range 30-87) in the non-epilepsy group (p=0.12). Median KBIT composite IQ score was 78 (range 40-118) in the epilepsy group and 96 (range 40-115) in the non-epilepsy group (p=0.41). One-third of all participants had ASD, with similar prevalence between epilepsy and non-epilepsy groups.
Conclusions:
Epilepsy in CAGS shows variable penetrance and onset, with diverse semiologies, most commonly absence seizures. Overall, epilepsy appears relatively benign and generally controlled with medication. Continued longitudinal follow-up will be critical to define the natural history and long-term outcomes.
Funding:
The Rosamund Stone Zander Translational Neuroscience Center Internal Pilot Grant and a donation from the Buffalano Family Fund supported this project.