Clinical Phenotypic Characterization of Na <sup>+</sup>-Taurocholate Cotransporting Polypeptide Deficiency in Humans: A Case-Control Study Based on <i>SLC10A1</i> Genotyping Analysis

Abstract

Background: Na+-taurocholate cotransporting polypeptide (NTCP) is a transporter protein encoded by the gene SLC10A1 and exclusively expressed in the hepatocyte to uptake bile salts. Although mice-based findings have substantially advanced the understanding of the pathophysiology of NTCP deficiency (NTCPD), this disease in humans was reported rarely so far, and due to lacking compelling evidences of case-control study, its genotypic and phenotypic characteristics remains far from being well understood. Methods: The SLC10A1 genotypes of all NTCPD patients were confirmed by screening for the prevalent variant c.800C>T and Sanger sequencing when necessary. The clinical presentations and laboratory changes were collected, reviewed and analyzed, and then compared with the relevant controls qualitatively and quantitatively. Findings: A total of 163 NTCPD patients were diagnosed while c.374dupG and c.682_683delCT were detected as 2 novel pathogenic mutations. Hypercholanemia was observed in 99.38% of the patients. Indirect hyperbilirubinemia in affected neonates while intrahepatic cholestasis of pregnancy (ICP) with increased risk of cesarean section and preterm birth in affected female adults both exhibited higher positive rates in comparison to controls. Moreover, during early infancy by 6 months of age, transient cholestatic jaundice, elevated liver enzymes and 25-hydroxyvitamin D (Vit D) deficiency were more commonly observed in patients than in controls. Interpretation: With hypercholanemia as a common clinical feature, NTCPD exhibited other age-dependent phenotypic presentations in humans, including ICP in female adults, transient cholestatic hepatitis in early infancy and indirect hyperbilirubinemia in neonates. The findings enriched the SLC10A1 mutation spectrum and provided comprehensive insights into the phenotypic characteristics of NTCPD Funding Statement: Our research was supported financially by National Natural Science Foundation of China (NSFC, Nos. 81570793, 81741080 and 81974057). Declaration of Interests: The authors declare no conflicts of interests. Ethics Approval Statement: This study adheres to the World Medical Association Declaration of Helsinki (WMADH2008), which was adopted by the 59th WMA General Assembly, Seoul, in October 2008, and has been approved by the Medical Ethical Committee, the First Affiliated Hospital, Jinan University (No.KY-2019-052). Written informed consents had also been obtained prior to the study from the research subjects or their guardians.