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. 2021 May 1;72(5):654-660.
doi: 10.1097/MPG.0000000000003094.

Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Saul J Karpen  1 , Binita M Kamath  2 , John J Alexander  3   4 , Ilia Ichetovkin  5 , Philip Rosenthal  6 , Ronald J Sokol  7 , Shelley Dunn  5 , Richard J Thompson  8 , James E Heubi  9
Affiliations

Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Saul J Karpen et al. J Pediatr Gastroenterol Nutr. .

Abstract

Objectives: Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis.

Methods: A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA).

Results: A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57% <1 year old) included 583 P variants, 79 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. The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG.

Conclusions: These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis.

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Conflict of interest statement

Conflicts of Interest: S.J.K.: Consultant for Albireo, Logic Bio, Intercept, Mirum, and Retrophin, Inc. B.M.K.: Consultant for Albireo, Retrophin, Inc., Shire, Mirum, DCI. J.J.A.: During the course of this study was a consultant for Retrophin, Inc and laboratory director at Emory/EGL. I.I.: During the course of this study was a full-time employee of Retrophin, Inc. P.R.: Consultant for Albireo, Alexion, Alnylam, Audentes, Intercept, and Retrophin, Inc. R.S.: Consultant for Albireo, Alexion, Shire, Mirum, and Retrophin, Inc. S.D.: Full-time employee of Retrophin, Inc. R.T.: Consultant for Retrophin, Inc, Shire, Mirum Albireo, Alnylam, Horizon Pharma, Sana Biotechnology, Qing Bile Therapeutics, and GenerationBio, and has stock options at Qing Bile Therapeutics and GenerationBio. J.E.H.: Equity interest in Asklepion, and consultant for Retrophin, Inc, Shire, Alnylam, Friesland Campina, Mirum, and Nordmark.

References

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