Combined Genetic and Transcriptional Study Unveils the Role of Gene Mutations in Congenital Diarrhea.

: Congenital diarrhea is persistent diarrhea that manifests during the neonatal period. Mutations in , which is crucial for triglyceride synthesis and lipid absorption in the small intestine, are causal factors for congenital diarrhea. In this study, we aimed to determine the value of tissue RNA sequencing (RNA-seq) for assisting with the clinical diagnosis of some genetic variants of uncertain significance. : We clinically evaluated a patient with watery diarrhea, vomiting, severe malnutrition, and total parenteral nutrition dependence. Possible pathogenic variants were detected using whole-exome sequencing (WES). RNA-seq was utilized to explore the transcriptional alterations in variants identified by WES with unknown clinical significance, according to the American College of Medical Genetics guidelines. Systemic examinations, including endoscopic and histopathological examinations of the intestinal mucosa, were conducted to rule out other potential diagnoses. : We successfully diagnosed a patient with congenital diarrhea and protein-losing enteropathy caused by a mutation and reviewed the literature of 19 cases of children with defects. The missense mutation c.620A>G, p.Lys207Arg located in exon 15, and the intronic mutation c.1249-6T>G in were identified by WES. RNA-seq revealed two aberrant splicing events in the gene of the patient's small intestinal tissue. Both variants lead to loss-of-function consequences and are classified as pathogenic variants of congenital diarrhea. : Rare variants were identified as pathogenic evidence of congenital diarrhea, and the detection of tissue-specific mRNA splicing and transcriptional effects can provide auxiliary evidence.