Diagnostic Yield of an Algorithm for Neonatal and Infantile Cholestasis Integrating Next-Generation Sequencing

J Pediatr. 2019 Aug:211:54-62.e4. doi: 10.1016/j.jpeds.2019.04.016. Epub 2019 May 31.

Abstract

Objective: To evaluate the performance of a diagnostic protocol for neonatal/infantile cholestasis in which the main clinical patterns steered the early use of different genetic testing strategies.

Study design: An observational study was conducted between 2012 and 2017 in a tertiary care setting on a prospective cohort of children with cholestasis occurring at ≤1 year of age and persisting ≥6 weeks, to measure the detection rate of underlying monogenic diseases. After the exclusion of biliary atresia, a clinically driven genetic testing was performed, entailing 3 different approaches with different wideness: confirmatory single-gene testing; focused virtual panels; and wide search through trio whole-exome sequencing.

Results: We enrolled 125 children (66 female, median age 2 months); 96 (77%) patients had hypocholic stools and were evaluated rapidly to exclude biliary atresia, which was the final diagnosis in 74 (59%). Overall, 50 patients underwent genetic testing, 6 with single confirmatory gene testing, 38 through panels, and 6 with trio whole-exome sequencing because of complex phenotype. The genetic testing detection rate was 60%: the final diagnosis was Alagille syndrome in 11, progressive familial intrahepatic cholestasis type 2 in 6, alpha-1-antitrypsin deficiency in 3, and progressive familial intrahepatic cholestasis type 3 in 2; a further 7 genetic conditions were identified in 1 child each. Overall, only 18 of 125 (14%) remained with an indeterminate etiology.

Conclusions: This protocol combining clinical and genetic assessment proved to be an effective diagnostic tool for neonatal/infantile cholestasis, identifying inherited disorders with a high detection rate. It also could allow a noninvasive diagnosis in children presenting with colored stools.

Keywords: Alagille syndrome; biliary atresia; diagnosis; etiology; familial cholestasis; genetic testing; infantile cholestasis; monogenic liver disease; neonatal cholestasis; next-generation sequencing.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Alagille Syndrome / diagnosis
  • Alagille Syndrome / genetics
  • Algorithms
  • Biliary Atresia / diagnosis
  • Biliary Atresia / genetics
  • Child
  • Child, Preschool
  • Cholestasis / diagnosis*
  • Cholestasis / genetics*
  • Cholestasis, Intrahepatic / diagnosis
  • Cholestasis, Intrahepatic / genetics
  • Exome
  • Feces
  • Female
  • Genetic Testing
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Phenotype
  • Prospective Studies
  • Tertiary Healthcare
  • alpha 1-Antitrypsin Deficiency / diagnosis
  • alpha 1-Antitrypsin Deficiency / genetics

Substances

  • ATP Binding Cassette Transporter, Subfamily B

Supplementary concepts

  • Cholestasis, progressive familial intrahepatic 1
  • Cholestasis, progressive familial intrahepatic 2
  • Cholestasis, progressive familial intrahepatic 3