The genetics of monogenic intestinal epithelial disorders

Abstract

Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.

Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant

“…These syndromes fall into the group of epithelial structure, trafficking, and polarity according to the most recent classification of monogenic intestinal epithelial disorders. 12 The homozygous pathogenic variant T186G (Y62*) for this case is a previously unpublished nonsense variant (leading to a premature stop codon) predicted to result in protein truncation or nonsense mediated decay (see Table 1). In addition, the histopathologic features of the gastrointestinal tract in patients with IDEDNIK syndrome have not been reported.…”

“…These syndromes fall into the group of epithelial structure, trafficking, and polarity according to the most recent classification of monogenic intestinal epithelial disorders. 12…”

Therapy Development for Microvillus Inclusion Disease using Patient-derived Enteroids

“…Microvillus Inclusion Disease (MVID) is a rare congenital diarrhea and enteropathy (CoDE) caused by lossof-function mutations in the motor protein Myosin Vb (MYO5B) (1)(2)(3)(4)(5) . In general, patients with severe loss of MYO5B function have profound diarrhea, intestinal fluid loss and nutrient malabsorption requiring parenteral nutrition and supplemental fluids to maintain growth and fluid status (4,6). Patients with MVID are difficult to manage with a number of clinical problems including acidosis, dehydration, central line infections and micronutrient deficiency.…”

Biallelic variants of the first Kunitz domain of SPINT2 cause a non‐syndromic form of congenital diarrhea and tufting enteropathy

“…Although many of these disorders are linked to altered immune system function, disruption of intestinal epithelial structure and function is a characteristic that unites all these diseases (Babcock et al, 2023).…”