31813
Autism Spectrum Disorder Associated with Mutations in Srcap Upstream of Those Associated with Floating-Harbor Syndrome Generate Overlapping Yet Distinct Functional DNA Methylation Signatures

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)

ABSTRACT WITHDRAWN

Background: Autism spectrum disorder (ASD) is an etiologically and phenotypically heterogeneous neurodevelopmental disorder. Genetic causes have been identified (>200 ASD-risk genes), but no single gene mutation accounts for >1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the many ASD-risk genes that function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. We have identified two individuals with ASD who carry variants of unknown significance (VUS) in the Snf2 Related CREBBP Activator Protein gene (SRCAP). SRCAP encodes the core catalytic component of the SRCAP complex, which is involved in chromatin remodelling and acts in the Notch signalling pathway, important during development. Heterozygous variants in exons 33 and 34 of SRCAP are known to cause a rare genetic disorder, Floating-Harbor Syndrome (FHS; OMIM #136140), although not all FHS cases have an identifiable genetic cause. FHS is characterized by distinctive facial features, short stature, intellectual and speech impairments, and delayed bone age. ASD is not commonly comorbid with FHS, but the two disorders share some overlapping physical, cognitive and behavioural features.

Objectives: Given that SRCAP functions as an epigenetic regulator within important developmental pathways, we investigated whether aberrant epigenetic marks, specifically DNA methylation (DNAm), contribute to the molecular pathophysiology of FHS and if such specific DNAm patterns will distinguish between the two phenotypes observed in individuals with independent variants in the same gene.

Methods: To test this, we assessed for genome-wide DNAm patterns using the Illumina MethylationEPIC array in whole blood DNA from patients with a clinical diagnosis of ASD and SRCAP VUS (n=2) or FHS and pathogenic SRCAP variants (n=3).

Results: Despite a small number of cases, we identified an FHS-specific DNAm signature comprised of >2,000 CpG sites (FDR corrected p-value<0.001) that distinctly separated FHS cases from age- and sex-matched neurotypical controls (n=59). Pathway analysis performed on the differentially methylated genes in this signature revealed enrichment in neuronal differentiation and fibronectin production, biological pathways relevant to the pathophysiology of FHS. The FHS DNAm signature was used to classify the two individuals with ASD in order to better interpret the pathogenicity of the SRCAP VUS, classifying them as intermediate between FHS signature cases and controls, reflecting the partially overlapping phenotypic features described.

Conclusions: In summary, we have demonstrated functional and biological utility of the FHS DNAm signature: it can be used as a molecular biomarker to inform pathogenicity of VUS and thus FHS diagnosis, and to elucidate the underlying biological mechanisms that will help us to better understand, diagnose and treat FHS and other disorders with overlapping features, such as ASD.

See more of: Epigenetics
See more of: Epigenetics