SLC10A1 variants causing NTCP deficiency in infants: clinical and functional characterization of a novel splice-site...

Sodium taurocholate cotransporting polypeptide (NTCP), the product of the SLC10A1 gene, is essential for hepatic bile acid (BA) uptake. Biallelic SLC10A1 defects resulting in NTCP deficiency have recently been identified as a cause of familial hypercholanemia in children, but clinical and functional data are lacking.

Three unrelated infants with neonatal or infantile cholestasis were recruited. Clinical data, laboratory results, and follow-up details were reviewed. SLC10A1 variants were identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing. An HEK293T minigene splicing assay was used to assess the functional consequences of the new splicing variant.

All three patients exhibited sustained hypercholanemia accompanied by varying degrees of elevated liver enzymes and decreased levels of fat-soluble vitamins. WES identified homozygous or compound heterozygous SLC10A1 variants in all three patients, including the frequent East Asian missense variant c.800 C > T (p.Ser267Phe), the rare frameshift variant c.722_723del (p.Ser241Cysfs*36), and a novel splice-site variant c.746 + 5G > T. The c.746 + 5G > T variant was predicted to affect splicing, and a minigene assay showed that this variant caused exon 3 skipping, which is predicted to result in a frameshift transcript. According to ACMG/AMP guidelines, c.722_723del variant was classified as "Pathogenic", and the c.746 + 5G > T variant was assessed as "Pathogenic" after incorporating functional evidence from the minigene assay.

This study broadens the variant spectrum of SLC10A1-related NTCP deficiency and highlights the value of functional testing in the assessment of novel splicing-site variants. Early genetic diagnosis may facilitate appropriate clinical management and help prevent unnecessary interventions.