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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]

Pemphigus foliaceus (PF) is a bullous autoimmune skin disease diagnosed through sera and skin analyses. PF severity is associated with maintained anti‐Dsg1 sera levels and its prognosis is unpredictable. MicroRNA (miRNA), dynamic regulators of immune function, have been identified as potential biomarkers for some autoimmune diseases. This study aimed to assess the miRNA expression of miR‐17‐5p, miR‐21‐5p, miR‐146a‐5p, miR‐155‐5p and miR‐338‐3p using quantitative real‐time PCR in peripheral blood mononuclear cells (PBMC) and lesional skin samples from untreated and treated PF patients (both remittent and chronic) over 3 months. Overall, miRNA expression was significantly higher in PBMC than in biopsy samples. Blood miR‐21 expression was increased in untreated patients compared to controls and had a diagnostic value with an AUC of 0.78. After 6 weeks, it decreased significantly, similar to anti‐Dsg1 antibodies and the PDAI score. In addition, a positive correlation was observed between cutaneous miR‐21 expression and the disease activity score. Conversely, cutaneous expressions of miR‐17, miR‐146a and miR‐155 were significantly higher in treated chronic patients compared to remittent ones. The cutaneous level of miR‐155 positively correlated with pemphigus activity, making it a potential predictive marker for patients' clinical stratification with an AUC of 0.86.These findings suggest that blood miR‐21 and cutaneous miR‐155 can be used as supplemental markers for PF diagnosis and activity, respectively in addition to classical parameters. [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]