Enteric anendocrinosis attributable to a novel Neurogenin-3 variant

• Published in: European journal of medical genetics 2020-09, Vol.63 (9), p.103981-103981, Article 103981
• Main Authors: Azab, Belal, Dardas, Zain, Rabab'h, Omar, Srour, Luma, Telfah, Hussam, Hatmal, Ma'mon M., Mustafa, Lina, Rashdan, Lana, Altamimi, Eyad
• Format: Article
• Language: English
• Subjects: Basic Helix-Loop-Helix Transcription Factors - chemistry; Basic Helix-Loop-Helix Transcription Factors - genetics; Binding Sites; Congenital diarrhea and enteropathies (CODEs); Diarrhea - congenital; Diarrhea - genetics; Diarrhea - pathology; Enteric anendocrinosis (EA); Homozygote; Humans; Infant; Malabsorption Syndromes - genetics; Malabsorption Syndromes - pathology; Male; Mutation, Missense; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Neurogenin-3 (NEUROG3); Simulation analysis; Whole Exome Sequencing; Whole-exome sequencing (WES)
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2020.103981

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that often present with severe diarrhea in the first weeks of life. Enteric anendocrinosis (EA), an extremely rare cause of CODE, is characterized by a marked reduction of intestinal enteroendocrine cells (EC). EA is associated with recessively inherited variants in Neurogenin-3 (NEUROG3) gene. Here we investigate a case of a male infant who presented with mysterious severe malabsorptive diarrhea since birth. Thorough clinical assessments and laboratory tests were successful to exclude the majority of differential diagnosis categories. However, the patient's diagnosis was not established until the genetic test using whole-exome sequencing (WES) was performed. We identified a novel homozygous missense disease-causing variant (DCV) in NEUROG3 (c.413C>G, p.Thr138Arg). Moreover, molecular dynamic simulation analysis showed that (p.Thr138Arg) led to a global change of the NEUROG3 orientation affecting its DNA binding capacity. To the best of our knowledge, this is the first time to apply WES to reach a differential diagnosis of patients with CODEs. Our study not only expands our knowledge about NEUROG3 variants and their clinical consequences but also proves that WES is a very effective tool for the diagnosis of CODEs. This might be of value in early diagnosis of diseases and prenatal CODEs detection.