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Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel–target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease‐causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP‐binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide‐binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis‐associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability. [ABSTRACT FROM AUTHOR]

• We described a novel ABCC2 mutation in two siblings with an infantile DJS. • We denied the genotype-phenotype largely reported in the neonatal/infantile DJS. • We identified, for the first time, a complex genotype in DJS cases. • We showed the utility of the NGS as an effective tool for an accurate genetic diagnosis of cholestasis. The Dubin Johnson Syndrome (DJS) occurs mostly in young adults but an early-onset of the disease has been reported in less common forms (Neonatal DJS and Infantile DJS). In this case, the clinical findings are of limit for the DJS diagnosis. Hence, the genetic testing remains the method of choice to provide an accurate diagnosis. In our study, we aimed to perform a genetic analysis for two siblings presented with an intrahepatic cholestasis before the age of 1 year to provide a molecular explanation for the developed phenotype. A Tunisian family, having two siblings, manifesting signs of a hepatopathy, was enrolled in our study. A molecular analysis was performed, using a panel-based next generation sequencing, supplying results that were the subject of computational analysis. Then, a clinical follow-up was carried out to assess the evolution of the disease. The genetic analysis revealed the presence of a novel missense c.4179G > T, (p.M1393I) mutation in ABCC2 gene associated with a substitution c.2789G > A (R930Q) in ATP8B1 gene. Predictive results consolidated the pathogenic effect of both variants. These results confirmed the DJS diagnosis in the studied patients. The clinical course of both patients fit well with the benign nature of DJS. We described here a novel ABCC2 mutation associated with a putative ATP8B1 modifier variant. This finding constituted the first report of a complex genotype in DJS. Hence, genetic analysis by a panel-based next generation sequencing permits an accurate diagnosis and the identification of putative variants that could influence the developed phenotype. [ABSTRACT FROM AUTHOR]

Abstract Introduction Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a chronic autosomal recessive disorder characterized by a wide spectrum of clinical severity generally related to the degree of pathogenicity of the causal sequence variation in ABCB 4 gene. Patients and methods The present study reports the molecular investigation by Next Generation Sequencing (NGS) of five related patients with PFIC3 disease followed by bioinformatic analysis. A biochemical follow-up is also performed to assess the response of the ursodeoxycholic acid treatment. Results The molecular results revealed complex genotype in homozygous state in all patients including a pathogenic c.1436C > T (P479L) variation in the ABCB4 gene and two well-known polymorphisms, the V444A in ABCB11 gene and the D19H in the ABCG8 gene. Although the presence of the same genetic background, all patients present the disease at different ages and clinical signs with a variable degree of clinical severity at diagnosis. Additionally, a differential outcome to the treatment has been pointed out. Conclusion Our results provide evidence regarding the putative intervention of modifier factors in the phenotypic variability reported for the first time in the PFIC3 disease and highlight the importance of an early administration of the UDCA as a good solution to ovoid the disease progression. Highlights • Identification of putative genetic modifiers in both ABCB11 and ABCG8 in the physiopathology of the PFIC3. • First description of phenotypic variability among PFIC3 patients with similar genetic background. • Revelation of new parameters influencing the response of PFIC3 patients to the UDCA treatment [ABSTRACT FROM AUTHOR]

Introduction West syndrome is a rare epileptic encephalopathy of early infancy, characterized by epileptic spasms, hypsarrhythmia, and psychomotor retardation beginning in the first year of life. Methods The present study reports the clinical, molecular and bioinformatic investigation in the three studied West patients. Results The results revealed a complex genotype with more than one mutation in each patient including the known mutations c.1910C > G (P2, P3); c.2372A > C in P3 and c.2395C > G in P1 and novel variants including c.616 G > A, shared by the three patients P1, P2 and P3; c.1403G > C shared by P2 and P3 and c.2288A > G in patient P1. Conclusions All the mutations were at somatic mosaic state and were de novo in the patients except ones (c.2372A > C). To our knowledge; the somatic mosaic state is described for the first time in patients with West syndrome. Five identified mutations were located in the C-terminal domain of the protein, while the novel mutation (c.616 G > A) was in the catalytic domain. Bioinformatic tools predicted that this latter is the most pathogenic substitution affecting 3D protein structure and the secondary mRNA structure. Complex genotype composed of different combinations of mutations in each patient seems to be related to the phenotype variability. [ABSTRACT FROM AUTHOR]