Congenital Diarrhea and Enteropathies Panel

Congenital diarrheas and enteropathies are rare inherited disorders characterized by persistent and severe diarrhea that often presents within the first few months of life. They are life-threatening, and requires medical intervention in the form of parenteral (IV) nutrition or hydration (Thiagarajah et al. 2018. PubMed ID: 29654747). At the molecular level, congenital diarrheas and enteropathies result directly from disruption of the intestinal epithelial cell function or from immune system dysfunction that secondarily impairs intestinal epithelium function (Canani et al. 2015. PubMed ID: 25782092). While intractable diarrhea is the major clinical feature, congenital diarrheas and enteropathies can present with extraintestinal manifestations as well as systemic disease (Thiagarajah et al. 2018. PubMed ID: 29654747). The worldwide incidence of most congenital diarrheas and enteropathies remains unknown, with some occurring more frequently in ethnic groups where consanguineous marriage is prevalent or in some geographic regions due to founder effects (Canani et al. 2015. PubMed ID: 25782092).

Chronic diarrheas represent a group of clinically and genetically heterogeneous disorders that are usually acquired through environmental exposures to allergens or infections, but may also be inherited (Thiagarajah et al. 2018. PubMed ID: 29654747). Studies suggest approximately 7 in 1,000 newborns admitted to neonatal intensive care units are admitted for diarrhea, of these approximately 57% of neonatal diarrhea cases are acquired, 13% are inherited, and the remainder are of an unknown etiology (Passariello et al. 2010. PubMed ID: 20518089).

A molecular diagnosis may aid in implementation of a therapeutic strategy for patients with a congenital diarrhea or enteropathy. For example, bone marrow transplant is a possible therapy in the context of immune system dysfunction (Glocker et al. 2009. PubMed ID: 19890111; Uhlig and Muise. 2017. PubMed ID: 28755896, Zheng et al. 2018. PubMed ID: 29788367), while dietary intervention or enzyme replacement treatments may be therapeutic in the context of intestinal epithelial cell dysfunction (van Rijn et al. 2018. PubMed ID: 29604290, Ye et al. 2018. PubMed ID: 30308536; Ma et al. 2019. PubMed ID: 31415402). In a recent study, 59.9% of patients with chronic diarrhea that was not likely to be acquired in early infancy were diagnosed with medically actionable genetic disorders (Ye et al. 2019. PubMed ID: 30894704). Patients and their families may also benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.

This test includes genes identified through literature, OMIM, and HGMD searches that have been reported to be associated with chronic diarrhea. Mendelian forms of diarrhea are most often inherited in an autosomal recessive (AR) manner but may also be inherited in an autosomal dominant (AD) or X-linked (XL) manner or arise de novo.

Among congenital diarrheas and enteropathies resulting from defects in intestinal epithelial cell function, the most prevalent may be due to defects in nutrient metabolism. For example, biallelic pathogenic variants in the SI gene result in congenital sucrose-isomaltase deficiency, a carbohydrate intolerance disorder characterized by the malabsorption of certain sugar molecules, with an estimated incidence of 1 in 5,000 in Europe (Swallow et al. 2001. PubMed ID: 11259342). Defects in enterocyte structure may also be among the most prevalent of congenital diarrheas and enteropathies. Biallelic pathogenic variants in the EPCAM gene, for example, impair proper enterocyte development and differentiation, resulting in autosomal recessive congenital tufting enteropathy, which has been estimated at an incidence of 1 in 50,000-100,000 births in Western Europe (Goulet et al. 2007. PubMed ID: 17448233). The prevalence of congenital diarrheas and enteropathies resulting from immune system dysfunction has not been established. However, in a recent study of patients with chronic diarrhea not likely to be acquired, 70% of patients with a molecular diagnosis had chronic diarrhea due to defects in immune system dysfunction (Ye et al. 2019. PubMed ID: 30894704).

A wide variety of causative variants in these genes have been reported including missense, nonsense, splicing, small insertions and deletions, large deletions and duplications, and complex rearrangements (Human Gene Mutation Database).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. This panel includes all of the genes identified through sequence analysis of the largest cohort of patients with a congenital diarrhea or enteropathy published to date. In this study, patients were included for an indication of chronic diarrhea in early infancy, while patients with acquired diarrheas (allergic disorders, neonatal necrotizing enterocolitis, and short bowel syndrome) were excluded. A genetic diagnostic rate of 75% among neonates, and 64% overall was achieved (Ye et al. 2019. PubMed ID: 30894704). 

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 96.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).