The most severe inherited disorders of smooth muscle cell function, referred to as multisystemic smooth muscle dysfunction syndrome (MSMDS) or megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), manifest in infancy with life-threatening defects in GI motility and are associated with mutations in the genes coding for components of the contractile machinery, including myosin light chain kinase (MYLK), SMA (ACTA2), and myosin heavy chain-11 (MYH11) (Moreno et al., 2016; Gamboa and Sood, 2019; Hashmi et al., 2021). Here, ACTA2 is linked to megacystis-microcolon-intestinal hypoperistalsis syndrome 1.