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.
Highlights
Congenital diarrheal disorders (CDDs) are a heterogeneous group of rare enteropathies characterized by early-onset, generally monogenic and inherited as an autosomal recessive trait [1]
The next-generation sequencing (NGS) panel that we have developed facilitates the diagnostic workup of CDDs, providing an unequivocal diagnosis in patients that often require to be rapidly managed with specific therapies to avoid a poor outcome [3]
The analysis of large gene panels frequently reveals a number of variants of uncertain significance (VUS) and novel variants not reported into reference databases
Summary
Congenital diarrheal disorders (CDDs) are a heterogeneous group of rare enteropathies characterized by early-onset, generally monogenic and inherited as an autosomal recessive trait [1]. In many CDD forms, diarrhea appears as the main symptom, while, in other cases, it appears as a corollary of a more complex, systemic, and multiorgan syndrome [2,3]. Most patients with CDDs require a rapid diagnosis since they need immediate and specific therapy to avoid a poor outcome [2,3]. Some CDDs appear with a specific clinical picture, and there are tests that allow us to quickly achieve the diagnosis, while, in other forms, the symptoms may overlap, and no tests other than genetic analysis are available [5]. For many CDDs, the disease-gene is known; molecular analysis can provide a rapid and specific diagnostic contribution [2]. Molecular analysis allows us to carry-out genetic counseling to the family, perform carrier analysis, and offer prenatal diagnosis to high-risk couples [8]
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