Genetic Spectrum of Cholestasis in Tunisia and Diagnostic Yield of Next-Generation Sequencing: Case Series of 70 Patients.

ABCB11

Genetic heterogeneity of cholestasis, dominated here by biallelic loss of function of ABCB11 causing progressive familial intrahepatic cholestasis type 2

Roughly a quarter of cholestasis cases have a genetic cause. The authors included patients referred for cholestasis over a ten-year period and analysed by a 292-gene panel and/or whole exome sequencing, comprising 70 patients from 66 unrelated families. A genetic diagnosis was established in 70% of families, with a diagnostic yield of molecular testing of 62%. The most frequent diagnoses were progressive familial intrahepatic cholestasis type 2 (n = 12), neonatal sclerosing cholangitis (n = 4), low phospholipid-associated cholelithiasis syndrome (n = 4) and Alagille syndrome (n = 4). ABCB11 was the most frequently mutated gene (15 of 46), with two recurrent variants, c.1062T>A p.(Tyr354Ter) and c.1826_1827dup p.(Ile610GlnfsTer45), found in six and four families respectively.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Two recurrent ABCB11 variants covering ten families in a Tunisian cohort of 66: this is exactly the kind of data that justifies targeted relative screening before broadening sequencing. North African populations remain massively underrepresented in allele frequency databases, and every such series directly improves ACMG classification of variants in our patients from these populations. The 62% yield should be read as that of a selected tertiary-centre referral pattern, not as a performance generalisable to all cholestasis.

Analysis by Dr Thibaut Benquey