GUCY2C – Congenital Sodium Diarrhea

Congenital sodium diarrhea (CSD) is a rare autosomal dominant secretory diarrhoea presenting in the neonatal period with intrauterine onset, high faecal sodium loss, dehydration, and abdominal distention. Excessive activation of intestinal receptor guanylate cyclase C (GC-C) disrupts sodium and water absorption, leading to volume depletion and electrolyte imbalance.

A recent case report described a neonate with abdominal distention, clear rectal fluid output, and dehydration who underwent diagnostic gene panel testing confirming a heterozygous GUCY2C variant associated with CSD. Initial management with parenteral nutrition provided electrolyte support; transition to full enteral feeding enabled symptomatic control through the first year of life, highlighting enteral management as an effective long-term strategy (PMID:37399692).

In a cohort of four unrelated infants with CSD, whole-exome sequencing and Sanger confirmation identified novel de novo missense mutations in GUCY2C. Functional assays in HEK293T cells demonstrated ligand-independent and ligand-stimulated increases in intracellular cyclic guanosine monophosphate, consistent with a gain-of-function mechanism (PMID:25994218). One patient later developed inflammatory bowel disease, suggesting variable extraintestinal manifestations.

Genetic evidence supports autosomal dominant inheritance with at least 5 probands (4 de novo and 1 familial) and no additional segregating relatives. All reported variants are missense activating mutations in intracellular domains of GC-C. This variant spectrum, combined with consistent de novo occurrence, yields a Moderate level of genetic support under ClinGen criteria.

Experimental data show robust functional concordance: activating GC-C mutations enhance cGMP accumulation in heterologous cells, recapitulating the diarrhoea phenotype via decreased sodium and water absorption and increased chloride secretion. These gain-of-function assays provide Moderate functional evidence for pathogenicity.

Integration of genetic and experimental findings confirms GUCY2C as a clinically valid gene for autosomal dominant CSD. Diagnostic testing for GUCY2C variants informs targeted management, including enteral electrolyte maintenance, and guides genetic counseling. Key Take-home: Activating GUCY2C mutations cause autosomal dominant CSD through GC-C gain-of-function, and enteral therapy can sustainably control symptoms.

References

• Nutrition (Burbank, Los Angeles County, Calif.) • 2023 • Successful therapy for congenital sodium diarrhea by enteral management: A case report. PMID:37399692
• Gut • 2016 • Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. PMID:25994218

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