P174: Pathological characteristics and alterations in proteomic profiles of preclinical models harboring patient-derived point mutation in the WDR45 gene

Introduction: Beck Fahrner syndrome (BEFAHRS) is a Mendelian disorder of the epigenetic machinery (MDEM).BEFAHRS is caused by deficiency of TET3, which plays a central role in DNA demethylation and is associated with a diagnostic DNA methylation episignature (DNA methylation pattern) in blood.Case studies of patients with BEFAHRS have linked the MDEM with intellectual impairment, developmental delay, hypotonia, features of autism, and in some cases, epilepsy.At present, the specific neurocognitive patterns associated with BEFAHRS remain undefined given the rarity of the syndrome.Deep phenotyping, including characterizing cognitive and behavioral profiles of the neurodevelopmental disorder, is an essential step towards determining potential outcome measures for future clinical trials and may shed light on epigenetic regulatory mechanisms in neurogenesis more broadly.Methods: A total of 9 individuals with BEFAHRS (6F, M age =12.77 years, SD=8.04, range= 5 to 26 years) completed a comprehensive cognitive test battery to assess for intellectual functioning, verbal and nonverbal reasoning, visuomotor skills, language, executive functioning, and verbal and visuospatial learning and memory.Caregivers also completed inventories to index daily adaptive behaviors (Adaptive Behavior Assessment 3rd Edition, ABAS) and executive functioning (Behavior Rating Inventory of Executive Function, BRIEF).All participants underwent exome sequencing that identified a variant in TET3 and subsequently underwent testing for the BEFAHRS episignature.Descriptive statistical analyses were used to identify cognitive areas that fell below average based on performance scores in the whole sample.These trends were then examined among those with positive vs negative BEFAHRS episignature.Wilcoxon signed rank tests were then applied to determine cognitive domains that are significantly weaker when compared to overall intellectual functioning in the whole sample, and Mann Whitney U tests for between group effects based on episignature (positive/negative BEFAHRS episignature).Results: On average, those with BEFAHRS, or variant in TET3, yielded below average scores in intellectual functioning, verbal reasoning and nonverbal reasoning, but performed in the low average range across other cognitive domains with the exception of impaired inhibition.Wilcoxon signed test indeed showed performance scores in inhibition were markedly lower as compared to overall intellectual functioning (Z=1.99,p=0.04).A general trend of better language and verbal skills were observed among those with a negative episignature than the participants with a positive episignature (Zs>2.20,ps<0.10).Of the whole sample, 66% of participants with BEFAHRS were rated 1.5 standard deviations below normative mean in overall adaptive behaviors (ABAS-3 General Adaptive Composite) and about 50% endorsed clinically significant problems with executive functioning (BRIEF Global Executive Composite).Both the positive and negative episignature groups yielded comparable trends as observed in the whole group.Conclusion: TET3 and associated DNA demethylation may play a prominent role in neurogenesis of prefrontal networks that underly executive functions.Moreover, the DNA methylation signature of BEFAHRS seems particularly tied to language and memory.Methylation testing should be considered for diagnostic clarification among those with an identified variant in TET3 but more preserved cognition.