多伦多儿童医院的Aleixo M. Muise小组在研究中取得进展。他们的最新研究提出了先天性腹泻和肠病的遗传结构。相关论文于2025年4月3日发表在《新英格兰医学杂志》上。

背景：新一代测序技术使精确治疗方法成为可能，改善了患有罕见疾病儿童的生活。先天性腹泻和肠病（CODEs）与高发病率和死亡率有关。虽然这些疾病的治疗在很大程度上是支持性的，但基于基因诊断的新兴靶向治疗包括特定饮食、药物治疗和手术干预。

方法：该课题组研究人员分析了疑似单基因先天性腹泻患儿的外显子组或基因组。利用细胞和斑马鱼模型，研究小组测试了新牵连基因变异的影响。

结果：在该课题组人员的129例疑似单基因先天性腹泻的婴儿先证病例系列中，该课题组人员在62例（48%）婴儿中发现了因果变异，包括一个新的始祖NEUROG3变异。利用细胞和斑马鱼模型，该团队还发现了三个与CODEs相关的新基因：GRWD1、MYO1A和MON1A，并对其进行了功能表征。

研究结果表明，该研究团队已经在大量病例系列患者中表征了CODE疾病的广泛遗传结构，并鉴定了三个与CODE相关的新基因。

附：英文原文

Title: The Genetic Architecture of Congenital Diarrhea and Enteropathy

Author: Zeenat Gaibee, Neil Warner, Katlynn Bugda Gwilt, Wenjuan Li, Rei Guan, Michael Yourshaw, Ryder Whittaker Hawkins, Christiane Zorbas, Jonathan St.-Germain, Mahdi Tabatabaie, Suli Mao, Vered Pinsk, Baruch Yerushalmi, Lee-kai Wang, Stanley F. Nelson, Laura Wozniak, Dror S. Shouval, Manar Matar, Amit Assa, Nathaniel Frost, Lissette Jimenez, Sari Acra, Thomas Walters, Stephen Mouat, Michael Li, Denis L.J. Lafontaine, Matthew Tyska, Brian Raught, Yaron Avitzur, Wayne I. Lencer, James R. Goldenring, Martín G. Martín, Jay R. Thiagarajah, Aleixo M. Muise

Issue&Volume: 2025-04-03

Abstract: BACKGROUND

Next-generation sequencing has enabled precision therapeutic approaches that have improved the lives of children with rare diseases. Congenital diarrhea and enteropathies (CODEs) are associated with high morbidity and mortality. Although treatment of these disorders is largely supportive, emerging targeted therapies based on genetic diagnoses include specific diets, pharmacologic treatments, and surgical interventions.

METHODS

We analyzed the exomes or genomes of infants with suspected monogenic congenital diarrheal disorders. Using cell and zebrafish models, we tested the effects of variants in newly implicated genes.

RESULTS

In our case series of 129 infant probands with suspected monogenic congenital diarrheal disorders, we identified causal variants, including a new founder NEUROG3 variant, in 62 infants (48%). Using cell and zebrafish models, we also uncovered and functionally characterized three novel genes associated with CODEs: GRWD1, MYO1A, and MON1A.

CONCLUSIONS

We have characterized the broad genetic architecture of CODE disorders in a large case series of patients and identified three novel genes associated with CODEs.

DOI: NJ202504033921309

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2405333