NEUROG3 – Congenital Malabsorptive Diarrhea 4

Biallelic loss-of-function variants in NEUROG3 underlie congenital malabsorptive diarrhea 4, characterized by severe secretory diarrhea in infancy, enteric anendocrinosis, and insulin-dependent diabetes mellitus. NEUROG3 encodes a basic helix-loop-helix transcription factor essential for enteroendocrine and pancreatic endocrine progenitor cell differentiation.

To date, at least 12 unrelated individuals from seven families have been reported with biallelic NEUROG3 variants presenting with congenital diarrhea and variable diabetes onset (PMID:16855267; PMID:21378176; PMID:28724572; PMID:32574610; PMID:31805014; PMID:36149814; PMID:21490072).

Inheritance is autosomal recessive, with parents of compound heterozygous probands unaffected, consistent with recessive segregation and no reported dominant phenotypes.

The variant spectrum includes homozygous nonsense (p.Glu74Ter), frameshift (p.Pro71fs), and missense changes such as c.413C>G (p.Thr138Arg) (PMID:32574610), with most alleles private to individual kindreds and no clear founder variants described.

Functional studies demonstrate that NEUROG3 variants abolish DNA binding to E-box elements, fail to activate the NEUROD1 promoter in vitro, and cannot induce endocrine lineage commitment in Xenopus embryos or human intestinal/pancreatic organoids, supporting a loss-of-function mechanism (PMID:16855267; PMID:31178402).

In summary, the association between NEUROG3 and congenital malabsorptive diarrhea 4 is definitive, supported by robust genetic and functional concordance over >15 years. NEUROG3 sequencing should be prioritized in neonates with unexplained severe diarrhea and later-onset diabetes to inform diagnosis, management, and genetic counseling.

References

• The New England Journal of Medicine • 2006 • Mutant neurogenin-3 in congenital malabsorptive diarrhea. PMID:16855267
• Diabetes • 2011 • Permanent Neonatal Diabetes and Enteric Anendocrinosis Associated With Biallelic Mutations in NEUROG3. PMID:21378176
• Pediatrics • 2017 • A New Case of Congenital Malabsorptive Diarrhea and Diabetes Secondary to Mutant Neurogenin-3. PMID:28724572
• European Journal of Medical Genetics • 2020 • Enteric anendocrinosis attributable to a novel Neurogenin-3 variant. PMID:32574610
• JCI Insight • 2020 • Null mutations of NEUROG3 are associated with delayed-onset diabetes mellitus. PMID:31805014
• Developmental Cell • 2019 • A Comprehensive Structure-Function Study of Neurogenin3 Disease-Causing Alleles during Human Pancreas and Intestinal Organoid Development. PMID:31178402
• The Journal of Clinical Endocrinology and Metabolism • 2022 • Novel Variants and Phenotypes in NEUROG3-Associated Syndrome. PMID:36149814

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