Abstract:
Many inherited conditions cause cholestasis in the neonate or infant. Next-generation
sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these
methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease
associations and improved our understanding of physiological bile secretion and flow. By helping to
define the molecular basis of certain cholestatic disorders, these methods have also identified new
targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the
same time, sequencing methods have presented new diagnostic challenges, such as the interpretation
of single heterozygous genetic variants. This article discusses those challenges in the context of
neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the
possibility of other causal variants not identified by the genetic screen used, and phenotypic variability
among patients with variants in the same genes. A prospective, observational study performed
between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2
and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an
example of potential benefits and challenges that clinicians could face having received a complex
genetic result. Further studies including large cohorts of patients with paediatric liver disease are
needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response
to, single heterozygous variants in cholestasis-associated genes.
