Further delineation of SLC9A3-related congenital sodium diarrhea

Abstract

Background: Congenital sodium diarrhea (CSD) is a rare enteropathy displaying both broad variability in clinical severity and genetic locus and allelic heterogeneity. Eleven CSD patients were reported so far with SLC9A3 variants that impair the function of the encoded intestinal sodium-proton exchanger 3 (NHE3).

Methods: We report a 4-year-old patient, born prematurely in the 35th week of gestation, with antenatal polyhydramnios and dilated intestinal loops, and with diarrhea of congenital onset, 2-6 times a day, and with polydipsia. She thrived age-appropriately under a normal family diet. Serum sodium levels were repeatedly normal but urinary sodium excretion was low. Exome sequencing revealed compound heterozygous variants in SLC9A3 as the likely cause of the congenital diarrhea.

Results: While exome sequencing did not reveal pathogenic or likely pathogenic variants in other genes that cause syndromic or non-syndromic forms of congenital and intractable diarrheas, we identified novel compound heterozygous variants in SLC9A3, a complex allele with two missense changes, NP_004165.2:p.[Ser331Leu;Val449Ile] and in-trans the missense variant p.(Phe451Ser).

Conclusion: The clinical phenotype here appears to localize to the milder end of the known CSD spectrum, and the identified variants suggest that this is the twelfth patient reported to date with CSD due to mutations in SLC9A3.

Keywords: CSD; NHE3; SLC9A3; compound heterozygous; parenteral nutrition; urinary sodium.

FIGURE 1

A genealogical tree of the investigated family is shown with the segregation of identified SLC9A3 variants, and Sanger sequencing traces depicting the identified SLC9A3 variants are shown beneath the tree, and finally a partial alignment of SLC9A3 orthologues from selected species shows the high conservation of mutated amino acid residues. C, control; P, patient.

FIGURE 2

Schematic of the NHE3 protein encoded by SLC9A3. Transmembrane domains (residues 1–454) and a cytosolic C‐terminal domain (residues 455–831) with known interactions as well as the sites of known variants identified in reported CSD patients are indicated. CHP, calcineurin homology protein; NHERF1/2, sodium hydrogen exchanger regulatory factor 1 and 2; P1–P11, patient 1–11, one whole‐gene deletion identified in patient P1 is not displayed; PKA, protein kinase A; SGK, serum and glucocorticoid kinase.