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Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing.

Abstract
Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029G>A, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.
AuthorsYe Yang, Jing Zhang, Li-Ting Li, Yi-Ling Qiu, Jing-Yu Gong, Mei-Hong Zhang, Cai-Hua Li, Jian-She Wang
JournalThe Journal of molecular diagnostics : JMD (J Mol Diagn) Vol. 23 Issue 11 Pg. 1491-1499 (11 2021) ISSN: 1943-7811 [Electronic] United States
PMID34543749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Bile Acids and Salts
  • gamma-Glutamyltransferase
  • Adenosine Triphosphatases
  • ATP8B1 protein, human
Topics
  • Adenosine Triphosphatases (genetics)
  • Bile Acids and Salts (blood)
  • Child
  • Child, Preschool
  • Cholestasis, Intrahepatic (blood, genetics)
  • DNA Copy Number Variations
  • Female
  • Gene Deletion
  • Gene Duplication
  • Genetic Testing (methods)
  • Humans
  • INDEL Mutation
  • Infant
  • Infant, Newborn
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Tandem Repeat Sequences (genetics)
  • Whole Genome Sequencing (methods)
  • gamma-Glutamyltransferase (blood)

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