Congenital diarrhoea and enteropathy genetics

Abstract

Congenital diarrhoea and enteropathy (CODE) disorders are rare and primarily affect the intestinal epithelium in infancy, leading to substantial morbidity and mortality. In a new multicentre study published in The New England Journal of Medicine, investigators in Canada and the USA characterized the genetic profile of CODE disorders via next-generation sequencing and identified known and novel pathogenic variants.

The researchers analysed the exomes or genomes of 139 infants (including 10 sibling pairs) with a clinical diagnosis of congenital diarrhoea. Next-generation sequencing data revealed variants in 24 known monogenic CODE genes, such as EPCAM and SLC9A3, including a novel variant in NEUROG3. Three CODE candidate genes, GRWD1, MYO1A and MON1A, were then functionally characterized in cell-based assays and zebrafish models. The researchers further classified those three genes through proximity-dependent biotin identification, showing that variants dysregulated intestinal pathways and protein function, such as goblet cell dysfunction, microvilli mislocalization and endosomal sorting.