SLC9A3 – Congenital Sodium Diarrhea

Congenital sodium diarrhea (CSD) is an autosomal recessive enteropathy characterized by intractable neonatal secretory diarrhea, antenatal polyhydramnios, intestinal dilation, and high fecal sodium and bicarbonate loss. SLC9A3 encodes the intestinal Na+/H+ exchanger NHE3, which is localized to the brush-border membrane of enterocytes and mediates electroneutral Na+ uptake. Pathogenic biallelic SLC9A3 variants impair NHE3-mediated sodium absorption, resulting in the clinical phenotype of CSD.

The phenotype typically begins in the third trimester with polyhydramnios (HP:0001561) and diffuse intestinal dilation, followed by life-long secretory diarrhea (HP:0002041), hyponatremia (HP:0002902), and metabolic acidosis (HP:0001942). Affected infants require early electrolyte supplementation to support growth, and long-term outcomes depend on early recognition and management.

Multiple case reports have described biallelic SLC9A3 variants in CSD patients. A male neonate presented with antenatal polyhydramnios and severe diarrhea due to a homozygous missense variant c.1039G>A (p.Glu347Lys) ([PMID:31276831]). A separate report detailed a compound heterozygous complex allele combining two NHE3 missense changes in a 4-year-old with milder CSD and polydipsia (HP:0001959), representing the twelfth patient described to date ([PMID:35775128]).

In a cohort study of 18 CSD patients from 16 families, nine individuals from eight unrelated families harbored recessive SLC9A3 mutations including missense, splice-site, truncating, uniparental disomy, and whole-gene deletion alleles ([PMID:26358773]). This series confirms genetic locus and allelic heterogeneity, with AR transmission supported by homozygous and compound heterozygous presentations.

Functional assays in NHE-null fibroblasts demonstrated that patient-derived SLC9A3 missense variants compromise NHE3 basal surface expression and Na+/H+ exchange activity while sparing acute regulatory responses, consistent with a loss-of-function mechanism ([PMID:26358773]). These in vitro findings align with the human phenotype and support pathogenicity.

No reports to date have disputed the SLC9A3–CSD association. Integrating genetic and functional data, biallelic SLC9A3 mutations result in reduced intestinal Na+ absorption and congenital secretory diarrhea. SLC9A3 genetic testing enables early diagnosis and guides electrolyte supplementation. Key take-home: SLC9A3 should be included in AR congenital diarrhea panels to facilitate prompt recognition and management of CSD.

References

• European Journal of Medical Genetics | 2019 | Congenital Sodium Diarrhea by mutation of the SLC9A3 gene. PMID:31276831
• Molecular Genetics & Genomic Medicine | 2022 | Further delineation of SLC9A3-related congenital sodium diarrhea. PMID:35775128
• Human Molecular Genetics | 2015 | Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. PMID:26358773

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