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NGS Gene Panel Analysis Revealed Novel Mutations in Patients with Rare Congenital Diarrheal Disorders
Maria Valeria Esposito1,2, Marika Comegna1,2, Gustavo Cernera1,2
1CEINGE-Biotecnologie Avanzate, 80145 Naples, Italy.
Insights
Rapid diagnosis of rare congenital diarrheal disorders (CDDs) is crucial. A new next-generation sequencing (NGS) panel for 92 CDD-related genes aids in quickly identifying genetic mutations, improving patient outcomes.
Area of Science:
- Genetics
- Pediatric Gastroenterology
- Molecular Diagnostics
Background:
- Congenital diarrheal disorders (CDDs) are inherited enteropathies presenting in early infancy.
- Accurate and timely diagnosis is essential for effective management and to prevent poor prognosis.
- Clinical presentation of CDDs often overlaps with non-genetic diarrheal conditions, complicating diagnosis.
Purpose of the Study:
- To develop and validate a next-generation sequencing (NGS) panel for diagnosing CDDs.
- To identify genetic mutations in patients suspected of having CDDs.
- To assess the utility of a multigene NGS panel for rapid and accurate CDD diagnosis.
Main Methods:
- Development of a next-generation sequencing (NGS) panel targeting 92 genes associated with CDDs.
- Analysis of DNA samples from patients with suspected CDDs, including specific conditions like sucrose-isomaltase deficiency and microvillous inclusion disease.
- Bioinformatic tools were employed to define the pathogenicity of identified mutations, including novel ones.
Main Results:
- The NGS panel successfully identified disease-causing mutations in all analyzed patients across various CDDs.
- Several novel mutations were discovered and their pathogenicity was confirmed using bioinformatic analyses.
- The study included patients with sucrose-isomaltase deficiency, microvillous inclusion disease, congenital tufting enteropathy, glucose-galactose malabsorption, and congenital chloride diarrhea.
Conclusions:
- A multigene NGS panel for CDD-related genes enables unequivocal and rapid genetic diagnosis.
- This diagnostic approach can reduce the need for invasive procedures in diagnosing pediatric enteropathies.
- The findings highlight the importance of genetic testing in managing rare congenital diarrheal disorders.
Abstract:
Congenital diarrheal disorders (CDDs) are early-onset enteropathies generally inherited as autosomal recessive traits. Most patients with CDDs require rapid diagnosis as they need immediate and specific therapy to avoid a poor prognosis, but their clinical picture is often overlapping with a myriad of nongenetic diarrheal diseases. We developed a next-generation sequencing (NGS) panel for the analysis of 92 CDD-related genes, by which we analyzed patients suspect for CDD, among which were (i) three patients with sucrose-isomaltase deficiency; (ii) four patients with microvillous inclusion disease; (iii) five patients with congenital tufting enteropathy; (iv) eight patients with glucose-galactose malabsorption; (v) five patients with congenital chloride diarrhea. In all cases, we identified the mutations in the disease-gene, among which were several novel mutations for which we defined pathogenicity using a combination of bioinformatic tools. Although CDDs are rare, all together, they have an incidence of about 1%. Considering that the clinical picture of these disorders is often confusing, a CDD-related multigene NGS panel contributes to unequivocal and rapid diagnosis, which also reduces the need for invasive procedures.
