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 impr...

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Autores principales:	Rebecca Jeyaraj, Kirsten McKay Bounford, Nicola Ruth, Carla Lloyd, Fiona MacDonald, Christian J. Hendriksz, Ulrich Baumann, Paul Gissen, Deirdre Kelly
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neonatal cholestasis infantile cholestasis next-generation sequencing heterozygous pathogenic variants Genetics QH426-470
Acceso en línea:	https://doaj.org/article/19e6850e82d44dfc96f2b4081fee6317
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spelling	oai:doaj.org-article:19e6850e82d44dfc96f2b4081fee63172021-11-25T17:42:33ZThe Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges10.3390/genes121118372073-4425https://doaj.org/article/19e6850e82d44dfc96f2b4081fee63172021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1837https://doaj.org/toc/2073-4425Many 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 (<i>ATP8B1</i>, <i>ABCB11</i>, <i>ABCB4</i>, <i>NPC1</i>, <i>NPC2</i> and <i>SLC25A13</i>) 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.Rebecca JeyarajKirsten McKay BounfordNicola RuthCarla LloydFiona MacDonaldChristian J. HendrikszUlrich BaumannPaul GissenDeirdre KellyMDPI AGarticleneonatal cholestasisinfantile cholestasisnext-generation sequencingheterozygous pathogenic variantsGeneticsQH426-470ENGenes, Vol 12, Iss 1837, p 1837 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neonatal cholestasis infantile cholestasis next-generation sequencing heterozygous pathogenic variants Genetics QH426-470
spellingShingle	neonatal cholestasis infantile cholestasis next-generation sequencing heterozygous pathogenic variants Genetics QH426-470 Rebecca Jeyaraj Kirsten McKay Bounford Nicola Ruth Carla Lloyd Fiona MacDonald Christian J. Hendriksz Ulrich Baumann Paul Gissen Deirdre Kelly The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges
description	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 (<i>ATP8B1</i>, <i>ABCB11</i>, <i>ABCB4</i>, <i>NPC1</i>, <i>NPC2</i> and <i>SLC25A13</i>) 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.
format	article
author	Rebecca Jeyaraj Kirsten McKay Bounford Nicola Ruth Carla Lloyd Fiona MacDonald Christian J. Hendriksz Ulrich Baumann Paul Gissen Deirdre Kelly
author_facet	Rebecca Jeyaraj Kirsten McKay Bounford Nicola Ruth Carla Lloyd Fiona MacDonald Christian J. Hendriksz Ulrich Baumann Paul Gissen Deirdre Kelly
author_sort	Rebecca Jeyaraj
title	The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges
title_short	The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges
title_full	The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges
title_fullStr	The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges
title_full_unstemmed	The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges
title_sort	genetics of inherited cholestatic disorders in neonates and infants: evolving challenges
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/19e6850e82d44dfc96f2b4081fee6317
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The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

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