Left–right patterning in congenital heart disease beyond heterotaxy

Abstract

Congenital heart defect is one of the most common structural birth defects in the human population. It is highly associated with heterotaxy, a birth defect involving randomized left–right patterning of visceral organ situs. Large scale mouse forward genetics have led to the finding of a central role for cilia in CHD pathogenesis, with some cilia and non‐cilia mutations causing CHD with heterotaxy. Interestingly, many of the mutations causing CHD with heterotaxy can give rise to three laterality outcomes comprising normal situs solitus, mirror symmetric situs inversus totalis, or randomized situs with heterotaxy. Given CHD is largely observed only with heterotaxy, this suggests a new paradigm is needed for investigating the genetics of CHD associated with heterotaxy. Furthermore, analysis of data from multiple large birth cohorts have independently confirmed a broader involvement of laterality disturbance in CHD. This was demonstrated by the common cooccurrence of rare laterality defects with CHD lesions of a wide spectrum. These findings suggest left–right patterning is tightly intertwined with the developmental processes that regulate cardiac morphogenesis and its disturbance may contribute to all types of CHD even in the absence of laterality defects.

Atypical Brain Asymmetry in Human Situs Inversus: Gut Feeling or Real Evidence?

“…Prevalence figures for heterotaxy are estimated at 1/8000-1/12,000 live births [12,16,17]. Although classic heterotaxy accounts for only 3% of all congenital heart defects, gene mutations causing heterotaxy are also known to result in isolated cardiovascular malformations with no other visceral abnormalities, suggesting that the real prevalence of genetic heterotaxy is probably higher [19,23]. Two general types of heterotaxy, called isomerism, are described, although their exact morphology and its resulting abnormalities vary from patient to patient [11,19].…”

Getting to the Heart of Left–Right Asymmetry: Contributions from the Zebrafish Model

“…The heart is particularly sensitive to disturbances in left-right patterning and the most severe symptoms of laterality disorders are related to defects in cardiac patterning [3]. The reason for this is perhaps two-fold: firstly, the heart plays such a pivotal role in our survival that anything affecting its function has dire consequences [4] and, secondly, the organ itself exhibits considerable asymmetry and is, therefore, highly sensitive to left-right patterning defects [5]. A range of laterality defects can affect the heart, and these include AV valve defects, atrial septal defects, ventricular septal defects, transposition of the great arteries, double-outlet right ventricle and outflow tract defects [6].…”

The twists and turns of left-right asymmetric gut morphogenesis

“…In many cases, these asymmetries are evolutionarily conserved and necessary for physiological function, indicating that the formation of LR asymmetry is an essential phase of vertebrate organogenesis. Indeed, abnormal LR axis formationa condition known as heterotaxyis associated with some of the most common and severe structural birth defects, including complex congenital heart defects (CHDs), intestinal malrotation, extrahepatic biliary atresia, asplenia/polysplenia and other anomalies (Bartram et al, 2005;Chinya et al, 2019;Desgrange et al, 2018;Gabriel and Lo, 2020;Kothari, 2014;Ticho et al, 2000). Therefore, understanding the mechanisms that shape individual organ lateralities is not only necessary for illuminating the morphogenesis of numerous organs but could also be crucial for explaining the etiology of a wide variety of birth defects.…”