Genetic Diagnostic Tools for Cholestasis

Several articles in a recent JPGN (May issue) delve into the topic of using genetic tools for the diagnosis of cholestatic conditions. The most important, in my view, of these articles is JPGN 2021; 72: 654-660. (Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults); congratulations to the lead author, my colleague Saul Karpen.

Key findings:

  • Between February 2016 and December 2017, 2171 results were reported. Median turnaround time was 21 days.
  • 583 pathogenic (P) variants, 79 likely pathogenic (LP) variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel.
  • The panel’s overall diagnostic yield was 12% (n = 265/2171) representing 32 genes with mutations identified (the panel tested up to 66 genes).
  • The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11SERPINA1ABCB4, and POLG. (Table 3 lists all of the findings)

Other reports in the same issue describe a normal-GGT cholestasis due to USP53 deficiency

My take: Genetic cholestasis panels and/or whole exome sequencing are very useful and are being incorporated earlier into diagnostic workups.

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