The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges.
The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges.
复制标题
DOI：
10.3390/genes12111837
复制
发表时间：
2021-11-21
期刊：
影响因子：
3.5
通讯作者：
Kelly D
中科院分区：
文献类型：
--
作者：
Jeyaraj R;Bounford KM;Ruth N;Lloyd C;MacDonald F;Hendriksz CJ;Baumann U;Gissen P;Kelly D
许多遗传性疾病会导致新生儿或婴儿胆汁淤积。下一代测序方法可以促进其中一些病例的快速诊断;这些方法在不明原因肝病患者中的应用也发现了新的基因-疾病关联，并提高了我们对生理性胆汁分泌和流动的理解。通过帮助确定某些胆汁淤积性疾病的分子基础，这些方法还确定了新的治疗靶点以及更有可能从特定治疗中获益的患者亚组。与此同时，测序方法提出了新的诊断挑战，例如解释单个杂合遗传变异。本文讨论了这些挑战的背景下，新生儿和婴儿胆汁淤积症，重点是在预测变异致病性的困难，其他致病变异的可能性，未确定的遗传筛选，并在相同的基因变异患者的表型变异。在2010-2013年期间进行的一项前瞻性观察性研究，对222名婴儿肝病患者的国际队列中的6个重要基因（ATP 8B 1，ABCB 11，ABCB 4，NPC 1，NPC 2和SLC 25 A13）进行了测序，作为临床医生可能面临的潜在益处和挑战的一个例子。需要进一步的研究，包括大型队列的儿童肝病患者，以澄清与胆汁淤积相关基因的单一杂合变异相关的表型谱，以及适当的临床反应。
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.
登录
查看更多内容
柑橘缺乏引起的新生儿肝内胆汁淤积症 (NICCD) 死亡的相关危险因素及临床意义
影响因子：
2.4
作者：
Abuduxikuer, Kuerbanjiang;Chen, Rui;Wang, Jian-She
通讯作者：
Wang, Jian-She
影响因子：
13.5
作者：
Byrne, Jane A.;Strautnieks, Sandra S.;Thompson, Richard J.
通讯作者：
Thompson, Richard J.
影响因子：
30.8
作者：
Gissen, P;Johnson, CA;Maher, ER
通讯作者：
Maher, ER
影响因子：
13.5
作者：
Deleuze, JF;Jacquemin, E;Hadchouel, M
通讯作者：
Hadchouel, M
影响因子：
5.1
作者：
ALAGILLE, D;ODIEVRE, M;DOMMERGUES, JP
通讯作者：
DOMMERGUES, JP