Genetic Mouse Models of Autism Spectrum Disorder Present Subtle Heterogenous Cardiac Abnormalities.

Assimopoulos, S.; Hammill, C.; Fernandes, D. J.; Spencer Noakes, T. L.; Zhou, Y.-Q.; Nutter, L. M.; Ellegood, J.; Anagnostou, E.; Sled, J. G.; Lerch, J. P.

doi:10.1101/2021.10.19.465007

bioRxiv · 10.1101/2021.10.19.465007

Genetic Mouse Models of Autism Spectrum Disorder Present Subtle Heterogenous Cardiac Abnormalities.

Assimopoulos, S.·Hammill, C.·Fernandes, D. J.·Spencer Noakes, T. L.·Zhou, Y.-Q.·Nutter, L. M.·Ellegood, J.·Anagnostou, E.·Sled, J. G.·Lerch, J. P.

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Abstract

BackgroundAutism Spectrum Disorder (ASD) and Congenital Heart Disease (CHD) are strongly linked on a functional and genetic level. Most work has been focused on neurodevelopmental abnormalities in CHD. Conversely, cardiac abnormalities in ASD have been less studied. In this work we investigate the prevalence of cardiac comorbidities relative to genetic contributors of ASD. MethodsUsing high frequency ultrasound imaging, we screened 9 mouse models with ASD-related genetic alterations (Arid1b(+/-), Chd8(+/-), 16p11.2 (deletion), Sgsh(+/-), Sgsh(-/-), Shank3 {Delta}exon 4-9(+/-), Shank3 {Delta}exon 4-9(-/-), Fmr1(-/-), Vps13b(+/-)), and pooled wild-type littermates (WT). Using a standardised imaging protocol, we measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, Peak E and A velocity ratio of mitral inflow, Velocity Time Integral (VTI) through the ascending aorta. ResultsMutant groups presented small-scale alterations in cardiac structure and function compared to WTs. A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in measures of structure (LV chamber diameter and anterior wall thickness, HR, AoD). When compared to WTs, they differed in both structure and function (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmrl(-/-), Arid1b(+/-). Among mutant groups, the groups differing most from others were 16p11.2 (deletion), Sgsh(+/-), Fmrl(-/-). Our results broadly recapitulate the associated clinical findings. LimitationsVarious genetically driven cardiac abnormalities occur early in life, so repeating this work in non-adult mice may be valuable. To identify possible sex differences, we must extend this work to female mice. The downsampling procedure used (total correlation calculation) must be verified. Only indirect comparison between our results and clinical literature is possible due to differing study designs. ConclusionsThe characteristic heterogeneity of ASD was recapitulated in the observed cardiac phenotype. The type of measures (morphological, functional) mutant groups differ in can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal cardiac abnormalities can impact normal development.

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Assimopoulos, S., Hammill, C., Fernandes, D. J., Spencer Noakes, T. L., Zhou, Y.-Q., Nutter, L. M., Ellegood, J., Anagnostou, E., Sled, J. G., Lerch, J. P.. 2021-10-19. Genetic Mouse Models of Autism Spectrum Disorder Present Subtle Heterogenous Cardiac Abnormalities.. https://doi.org/10.1101/2021.10.19.465007

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