Abstract
Background Autism Spectrum Disorder (ASD) and Congenital Heart Disease (CHD) are strongly linked on a functional and genetic level. Most work has been focused on the neurodevelopmental abnormalities in CHD, whereas the investigation of cardiac abnormalities (CHD or not) in ASD has been more limited. In this work we investigate the prevalence of cardiac comorbidities relative to genetic contributors of ASD.
Methods Using high frequency ultrasound imaging, we screened 9 mouse models with ASD-related genetic alterations (Arid1b(+/-), Chd8(+/-), 16p11.2 (deletion), Sgsh(+/-), Sgsh(-/-), Shank3 Δexon 4-9(+/-), Shank3 Δexon 4-9(-/-), Fmr1(-/-), Vps13b(+/-)), along with pooled wild-type littermates (WT). Using a standardised imaging protocol, the cardiac morphological and functional parameters measured were thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, LV fractional shortening, heart rate (HR), aorta diameter (AoD), LV stroke volume and cardiac output.
Results Small-scale alterations in cardiac structure and function were found in the mutant groups compared to WTs. When mutant groups were compared to each other, a greater number of significant differences was observed than when mutant groups were compared to WT controls. Mutant groups differed primarily in measures of structure (LV chamber diameter and anterior wall thickness, HR, AoD), while when compared to WT controls, they differed in both structure and function (LV anterior wall thickness and thickening, LV chamber diameter and fractional shortening, HR). The mutant groups with most differences to WT controls are 16p11.2 (deletion), Fmr(-/-), Arid1b(+/-). Among mutant groups, the groups differing most from the others were 16p11.2 (deletion), Sgsh(+/-), Fmr1(-/-).
Our results recapitulate the clinical findings associated with each genetic mutation and broadly with ASD, to the extent that a direct comparison is possible. Additionally, our protocol was verified as an effective screening protocol capturing various dimensions of cardiac function.
Conclusions The characteristic heterogeneity of ASD was recapitulated in the cardiac phenotype of ASD-models. However, determining whether certain mutant groups differ in morphological or functional measures (as a general category) can offer insight regarding common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal cardiac abnormalities can impact normal development.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- ASD
- Autism Spectrum Disorder
- CHD
- Congenital Heart Disease
- UBM
- Ultrasound Bio-Microscopy
- LV
- Left Ventricle
- WT
- Wild-Type
- HET
- Heterozygous (+/-)
- HOM
- Homozygous (-/-)
- AoD
- Aorta Diameter
- HR
- Heart Rate
- LVAWed
- Left Ventricular Anterior Wall Thickness at End-Diastole
- LVAWes
- Left Ventricular Anterior Wall Thickness at End-Systole
- LVEDD
- Left Ventricular Chamber Diameter at End-Diastole
- LVESD
- Left Ventricular Chamber Diameter at End-Systole
- LVPWed
- Left Ventricular Posterior Wall Thickness at End-Diastole
- LVPWes
- Left Ventricular Posterior Wall Thickness at End-Systole
- LVAWT
- Left Ventricular Anterior Wall Thickening
- LVPWT
- Left Ventricular Posterior Wall Thickening
- FS
- Fractional Shortening
- CO
- Cardiac Output
- LVSV
- Left Ventricular Stroke Volume
- sys
- systole
- di
- diastole
- PCA
- Principal Component Analysis
- MRI
- Magnetic Resonance Imaging
- ECG
- Electrocardiography