The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

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.

Compound Heterozygous MYO5B Mutation, a Cause of Infantile Cholestasis: A Case Report

“…Our patient had most of the clinical and biochemical features in addition to the observed genetic variation to help us diagnose MYO5B cholestasis. 2 Apart from cystic fibrosis and alpha 1 antitrypsin deficiency, PFIC syndromes represent important genetic disorders of infantile cholestasis. It has been subclassified into various disease patterns based on specific bile transporter defects.…”

“…1 Genetic mutation accounting for 20-25% of cases of cholestasis represents the second most common group of illnesses after biliary atresia. 2 Progressive familial intrahepatic cholestasis (PFIC) due to impaired biliary canalicular transport is a common monogenic cholestatic illness, although newer mutations with a similar phenotype have been identified. Myosin 5B (MYO5B) cholestasis is one such disorder exact incidence of which is not yet known due to the paucity of studies.…”

Protocols of Investigation of Neonatal Cholestasis—A Critical Appraisal

“…Moreover, phenotypic variability among patients with the same pathogenic variant is a recognized interpretation difficulty. The role of heterozygous pathogenic variants in the development of NC gives rise to additional difficulties in the correct interpretation of NGS [ 83 ].…”

The cholestatic infant: updates on diagnosis and genetics

“…Monogenic defects are a cause of neonatal cholestasis in 25-50% of cases [9 ▪ ]. Genetic diseases such as Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), cystic fibrosis, alpha1 antitrypsin deficiency and other metabolic disease can have similar presentations making diagnosis challenging.…”