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

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Abstract
Cholestasis is caused by genetic disorders in 25% of cases. Our study aimed to describe the clinical and genetic profile of cholestasis and to demonstrate the importance of next‐generation sequencing (NGS) in the etiologic diagnosis of genetic cholestasis. We included patients referred for cholestasis over a 10‐year period. Molecular studies using NGS consisted of a 292‐gene panel and/or whole exome sequencing. Our cohort included 70 patients from 66 unrelated families. A genetic diagnosis was established in 70% of the families. The most common diagnoses were Type 2 progressive familial intrahepatic cholestasis ( n = 12), neonatal sclerosing cholangitis ( n = 4), low phospholipid‐associated cholelithiasis syndrome ( n = 4), and Alagille syndrome ( n = 4). The ABCB11 gene was most frequently mutated (15/46), with two recurrent variants, c.1062T>A (p.Tyr354*) and c.1826_1827dup (p.Ile610Glnfs*45), found in six and four families, respectively. Our results showed a 62% diagnostic yield of molecular testing using NGS in cholestasis. An accurate diagnosis was key to providing appropriate genetic counseling, guiding screening of variant carriers, and prenatal diagnosis.

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