NEW YORK – An international team has identified genetic variants in new and known genes linked to a group of rare inherited diarrhea and intestinal conditions that can lead to poor growth, along with increased morbidity and mortality in affected infants and children.
"Congenital diarrhea and enteropathies (CODEs) are a group of rare disorders that primarily affect the function of intestinal epithelial cells, leading to infant-onset diarrhea and poor growth," co-senior and co-corresponding author Aleixo Muise, a pediatrician and gastroenterologist affiliated with the University of Toronto and the Hospital for Sick Children and his colleagues wrote in a paper published in the New England Journal of Medicine on Wednesday.
"Although treatment of these disorders is largely supportive," they explained, "emerging targeted therapies based on genetic diagnoses include specific diets, pharmacologic treatments, and surgical interventions."
Together with investigators from Canada, the US, Israel, and New Zealand, Muise presented findings from a multicenter exome and whole-genome sequencing study focused on finding single-gene culprits in 129 infants suspected of suffering from CODE.
"Overall, we demonstrate the usefulness of next-generation sequencing as a powerful tool to identify known and novel pathogenic variants that cause congenital diarrhea," the authors wrote.
In 62 of the 129 CODE cases from "Pediatric Congenital Diarrhea and Enteropathies Consortium" (PediCODE) sites, the sequence analyses led to causal variants in at least one of the two dozen genes previously linked to monogenic CODE. Four of the cases appeared to be X-linked disorders, while the remaining 58 cases were autosomal recessive forms of CODE.
While epithelial trafficking and polarity genes such as EPCAM, MYO5B, TTC7A, and SKIV2L were most frequently affected, the investigators also uncovered suspicious variants in several other known CODE genes involved in processes such as immune cell regulation, nutrient and electrolyte transport, nutrient metabolism, and enteroendocrine cell development.
Along with the 62 probands carrying pathogenic variants, the team tracked down shared pathogenic variants in eight affected siblings, bringing the diagnosed CODE cases up to 70.
In their search for previously undetected CODE contributors, meanwhile, the researchers unearthed a founder mutation in the enteroendocrine cell development gene NEUROG3, which was linked to a CODE condition called enteric anendocrinosis in four affected infants from three families with Bedouin ancestry.
Through a series of follow-up functional analyses in CRISPR-Cas9 gene-edited cell lines and zebrafish models, the team also evaluated suspected CODE contributors in three genes not previously associated with the condition: the ribosomal subunit assembly gene GRWD1, the myosin gene MYO1A, and the secretory trafficking gene MON1A. Their results demonstrated that alterations in these candidate genes could impact intestinal processes.
Though they cautioned that it "is possible that some variants in genes associated with CODEs escaped identification by exome sequence analysis," the authors suggested that the current study provides a look at the "landscape of variants and heritability" behind CODE conditions.
Their diagnostic yield of approximately 50 percent was higher than the yield of 4 percent observed in a previous genetic study of inflammatory bowel disease and "similar to the high yield observed in some studies of neuromuscular disorders," the authors reported.