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Beyond IBD: the genetics of other early-onset diarrhoeal disorders
Lorraine Stallard1, Iram Siddiqui2, Aleixo Muise3,4,5
1SickKids Inflammatory Bowel Disease Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Insights
Severe childhood diarrhoeal disorders, often from birth, have genetic causes impacting the gut and beyond. Genomic studies reveal new mutations and potential treatments like stem cell transplants.
Area of Science:
- Pediatric Gastroenterology
- Human Genetics
- Immunology
Background:
- Diarrhoeal disorders in early childhood present significant morbidity and mortality, extending beyond inflammatory bowel diseases.
- These conditions can manifest with gastrointestinal, extraintestinal, immunodeficiency, and endocrinopathy symptoms.
- Genomic advancements have identified numerous genetic defects underlying these disorders.
Purpose of the Study:
- To provide an updated overview of genes implicated in early-onset diarrhoeal disorders.
- To focus on recently identified gene defects associated with protein-losing enteropathy.
- To explore the pathophysiology of the intestinal mucosa in these conditions.
Main Methods:
- Review of current literature on genetic defects in early-onset diarrhoeal disorders.
- Analysis of genomic findings and genotype-phenotype correlations.
- Discussion of functional studies using model systems like patient-derived organoids.
Main Results:
- Genomic analysis has identified new mutations contributing to severe early-onset diarrhoea.
- Precision treatments, including hematopoietic stem cell transplant, are emerging.
- Challenges remain in establishing clear genotype-phenotype correlations.
Conclusions:
- Understanding gene defects is crucial for characterizing early-onset diarrhoeal disorders.
- Patient-derived organoids offer a platform for studying disease mechanisms.
- Further research is needed to fully elucidate genotype-phenotype relationships and optimize therapeutic strategies.
Abstract:
Diarrhoeal disorders in childhood extend beyond the inflammatory bowel diseases. Persistent and severe forms of diarrhoea can occur from birth and are associated with significant morbidity and mortality. These disorders can affect not only the gastrointestinal tract but frequently have extraintestinal manifestations, immunodeficiencies and endocrinopathies. Genomic analysis has advanced our understanding of these conditions and has revealed precision-based treatment options such as potentially curative haematopoietic stem cell transplant. Although many new mutations have been discovered, there is frequently no clear genotype-phenotype correlation. The functional effects of gene mutations can be studied in model systems such as patient-derived organoids. This allows us to further characterise these disorders and advance our understanding of the pathophysiology of the intestinal mucosa. In this review, we will provide an up to date overview of genes involved in diarrhoeal disorders of early onset, particularly focussing on the more recently described gene defects associated with protein loosing enteropathy.
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