Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level

PFIC4 is a chronic liver disease which cannot be diagnosed based on clinical and biochemical findings with an unpredictable evolution. Here, we reported three consanguineous families with 9 children suffering from intrahepatic cholestasis with low GGT-activity. Three probands were chosen to undergo genetic testing. In silico analyses were conducted to assess the functional impact of the identified variant, along with variants occurring at highly conserved positions within the protein. Additionally, close clinical monitoring was carried. Targeted-NGS sequencing ruled out the diagnosis of PFIC1 and PFIC2. Subsequently, WES allowed the establishment of PFIC4 diagnosis for the three families through the identification of a homozygous TJP2 variant p. Gly532Arg classified as likely pathogenic with a structural damage predicted based on biomolecular modeling and simulation analysis. In-depth in silico analysis of 90 nsSNPs occurring in highly conserved residues in PDZ domains showed 14 ones seems to be relevant in the clinical practice. Clinically, a pronounced phenotypic variability is noted. In conclusion, our study described a homozygous missense PFIC4-related variant with a highlight on the pathogenic power of such types of variants. The clinical evaluation provided information about the importance of close monitoring to prevent liver failure and clarified the unexpected course of PFIC4.