3 research outputs found
Investigations into the genetic causes of liver disease using molecular genetic technologies
DNA sequencing technologies have developed quickly in the last decade, and new methodologies have moved into clinical practice. These can been used to investigate genetic causes of neonatal cholestasis. Neonatal cholestasis can be life-threatening and has a varied etiology.
In chapter 3, a targeted next generation sequencing (tNGS) assay was designed and assessed for suitability for detection of known mutations in genes associated with cholestasis. In chapter 4, this was used to screen over 200 infants presenting with liver disease for mutations in the (ATP8B1), (ABCB11), (ABCB4), (NPC1), (NPC2) and (SLC25A13) genes. Diagnoses were made in 9% and single heterozygous mutations were in 9% of cases. In chapter 5, patients suspected of PFIC-related disease werE tested for mutations in the (ATP8B1), (ABCB11) and (ABCB4) genes. This study uncovered 27 novel sequence variants, including 22 in UK patients, expanding the known mutation spectrum of these disorders. In chapter 6, patients suspected of NPC and were tested for mutations in (NPC1) and (NPC2), or (SLC25A13), respectively. These studies have identified 134 novel NPC mutations and 4 novel CD mutations.
Current and future DNA sequencing methods are discussed, as are new diagnostic strategies for genetically heterogeneous conditions like infantile liver disease
The genetics of inherited cholestatic disorders in neonates and infants : evolving challenges
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.Actelion Pharmaceuticals Ltd.; the MRC Biomedical Catalyst Award; the German Federal Ministry for Education and Research (BMBF) via the Hereditary Intrahepatic Cholestasis Translational Network; NIHR Academic Clinical Fellowship.https://www.mdpi.com/journal/genesam2022Paediatrics and Child Healt