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. 2021 Nov 16;22(22):12354.
doi: 10.3390/ijms222212354.

The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model

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The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model

Katherine C MacKenzie et al. Int J Mol Sci. .

Abstract

Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested-whole blood, dermal fibroblasts or saliva-but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to 'missing heritability' in developmental defects.

Keywords: Enteric Nervous System; Hirschsprung disease; developmental defects; gastrointestinal disease; missing heritability; motility disorder; somatic mutation.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the study design, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Developmental lineage tree highlighting where each of the three germ layers branch is from and what structures and organs they form or contribute to. Blood samples would be mesodermal, saliva samples would contain leukocytes of mesodermal origin and epithelial cells of ectodermal origin from the surface ectoderm [22], and unsorted gut samples would contain derivatives of all three germ layers, with ectodermal neural crest making up for the minority of cells. This figure was adapted from LifeMap (http://discovery.lifemapsc.com (accessed on 16 November 2018)).
Figure 2
Figure 2
Schematic representation of early embryonic development. (A) First divisions and differentiations of the developing embryo, depicting the formation of the three germ layers and the neural crest cells. (B) The highly proliferative and migratory ectodermal neural crest, begins to enter the endodermal gut tube at week 4 of human gestation. Some of these cells will also contribute to the neural cells of the lungs and the pancreas. (C) Cross section of the colon to highlight contribution from all three germ layers, with the lowest contribution being from ectoderm/neural crest. (D) Legend of cell types and their origins.
Figure 3
Figure 3
Proposed models of somatic mutations leading to HSCR. Each model shows four developmental stages, from initial ENCC migration into the gut tube (i), further migration and proliferation (ii), initial formation of ganglia (iii), to final colonization and ganglia formation (iv). (A) In the non-selective clonal growth and division model, the variant brings no competitive advantage or disadvantage, during migration or proliferation. However, this may lead to decreased differentiation or maturation capacity, for example. (B) In the selective advantage model, the variant confers a proliferative or migratory advantage to the cells, allowing them to out-compete the wild-type cells. However, due to early differentiation, altered subtype specification or inability to follow extracellular signals, the cells are unable to reach the distal portion of gut. (C) In the selective disadvantage model, the variant affects migration of ENS precursors, or the viability of the cells. As a consequence, the speed of the migratory wavefront is affected, leading to failure of ENCCs to colonize the distal colon. Apoptosis can also occur at some stage of migration or differentiation, resulting in decreased total cell count, that is insufficient to fully colonize the length of the gut tube. This is the most likely model that would result in a HSCR phenotype. Purple dots represent ENCCs with “normal” genotype; red dots represent ENCCs that have acquired a somatic variant.

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