Lateral thinking in syndromic congenital cardiovascular disease

Abstract

Syndromic birth defects are rare diseases that can present with seemingly pleiotropic comorbidities. Prime examples are rare congenital heart and cardiovascular anomalies that can be accompanied by forelimb defects, kidney disorders and more. Whether such multi-organ defects share a developmental link remains a key question with relevance to the diagnosis, therapeutic intervention and long-term care of affected patients. The heart, endothelial and blood lineages develop together from the lateral plate mesoderm (LPM), which also harbors the progenitor cells for limb connective tissue, kidneys, mesothelia and smooth muscle. This developmental plasticity of the LPM, which founds on multi-lineage progenitor cells and shared transcription factor expression across different descendant lineages, has the potential to explain the seemingly disparate syndromic defects in rare congenital diseases. Combining patient genome-sequencing data with model organism studies has already provided a wealth of insights into complex LPM-associated birth defects, such as heart-hand syndromes. Here, we summarize developmental and known disease-causing mechanisms in early LPM patterning, address how defects in these processes drive multi-organ comorbidities, and outline how several cardiovascular and hematopoietic birth defects with complex comorbidities may be LPM-associated diseases. We also discuss strategies to integrate patient sequencing, data-aggregating resources and model organism studies to mechanistically decode congenital defects, including potentially LPM-associated orphan diseases. Eventually, linking complex congenital phenotypes to a common LPM origin provides a framework to discover developmental mechanisms and to anticipate comorbidities in congenital diseases affecting the cardiovascular system and beyond.

Rbm8a deficiency causes hematopoietic defects by modulating Wnt/PCP signaling

“…Independent of underlying molecular mechanism, establishing a developmental connection between affected cell types in syndromic congenital disease provides a potent framework to expand diagnosis, phenotype assessment, and long-term care of affected patients. The multilineage potential of early LPM provides a developmental concept to connect seemingly disparate syndromic phenotypes as outlined above and to potentially regard them as LPM diseases 21 . rbm8a perturbation in zebrafish has increasingly pleiotropic defects as described here and in previous work 14 , in line with Rbm8a protein function in the ubiquitously deployed EJC that regulates diverse mRNA biology 9,12,78,129 .…”

“…Independent of underlying molecular mechanism, establishing a developmental connection between affected cell types in syndromic congenital disease provides a potent framework to expand diagnosis, phenotype assessment, and long-term care of affected patients. The multi-lineage potential of early LPM provides a developmental concept to connect seemingly disparate syndromic phenotypes as outlined above and to potentially regard them as LPM diseases 21 .…”

“…Hypomorphic perturbation of RBM8A in TAR Syndrome could therefore impact genes involved in a shared developmental process at the base of blood, limb, heart, and kidney development. The diversity of LPM cell fates could explain complex, yet developmentally connected co-morbidities of syndromic congenital anomalies as LPM diseases that result from early patterning defects 21 . By affecting blood, forelimbs, heart, and kidneys, the spectrum of TAR syndrome phenotypes seems to predominantly affect tissues of LPM origin.…”

From mechanisms of heart failure to clinical heart success

“…Thus, research into cardiac development and disease mechanisms is essential to better understand the underlying causes of congenital heart defects, particularly because these relationships are not always obvious. Underscoring this complexity, a Review from Christian Mosimann's group summarises how defects in lateral plate mesoderm development drive syndromic congenital defects of multiple organs, including the heart ( Kocere et al, 2023 ), and a Research article from Lelièvre et al (2023) analyses how mutations in endoglin that are linked to a rare vascular developmental disorder cause congestive heart failure.…”