Trio exome sequencing in individuals with CAKUT identifies de novo variants in potential novel candidate genes in 19.62.

IF 6.6 1区医学 Q1 GENETICS & HEREDITY

Genetics in Medicine Pub Date : 2025-04-10 DOI:10.1016/j.gim.2025.101432

Lea Maria Merz, Caroline M Kolvenbach, Chunyan Wang, Nils David Mertens, Steve Seltzsam, Bshara Mansour, Bixia Zheng, Sophia Schneider, Luca Schierbaum, Selina Hölzel, Daanya Salmanullah, Dalia Pantel, Gina Kalkar, Dervla M Connaughton, Nina Mann, Chen-Han Wilfred Wu, Franziska Kause, Makiko Nakayama, Rufeng Dai, Ronen Schneider, Florian Buerger, Camille Nicolas-Frank, Kirollos Yousef, Katharina Lemberg, Ken Saida, Seyoung Yu, Izzeldin Elmubarak, Gijs A C Franken, Kraisoon Lomjansook, Alina Braun, Stuart B Bauer, Nancy M Rodig, Michael J G Somers, Avram Z Traum, Deborah R Stein, Ankana Daga, Michelle A Baum, Ghaleb H Daouk, Hazem S Awad, Loai A Eid, Sherif El Desoky, Mohammed A Shalaby, Jameela A Kari, Said Ooda, Hanan M Fathy, Neveen A Soliman, Marwa Nabhan, Safaa Abdelrahman, Alina C Hilger, Shrikant M Mane, Michael A Ferguson, Velibor Tasic, Shirlee Shril, Friedhelm Hildebrandt

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引用次数: 0

Abstract

Purpose: Congenital anomalies of the kidney and urinary tract (CAKUT) encompass heterogenous malformations arising from defective nephrogenesis. To date, approximately 50 monogenic genes are known to cause CAKUT if mutated. Recent studies show the impact of de novo variants in genetic disease etiology. Hence, this study aimed to identify potential novel CAKUT disease genes with de novo variants.

Methods: We performed trio-based exome sequencing (ES) in 209 families with CAKUT to detect novel candidate disease genes.

Results: Trio analysis yielded in the identification of CAKUT candidate genes in 96 of 209 trio families (45.93%). In 41 of 209 cases, we detected strong de novo variants in 45 potential novel CAKUT candidate genes (19.62%). We developed a prioritization approach that highlights a truncating de novo variant in SOX13 (HGNC:11192) as a promising cause for CAKUT. In addition, further allele carriers for the candidate gene CHD1L (HGNC:1916) were identified, thus supporting the role of CHD1L in the pathogenesis of CAKUT.

Conclusion: We conclude that de novo variants in potential novel CAKUT candidate genes contribute to the disease etiology and present SOX13 as a potential novel cause for CAKUT.

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CAKUT个体的三重奏外显子组测序在19.62中发现了潜在的新候选基因的从头变异。

目的：先天性肾和尿路异常（CAKUT）包括由肾发生缺陷引起的异质畸形。迄今为止，已知约有50个单基因基因在发生突变时可导致CAKUT。最近的研究显示了新生变异在遗传疾病病因学中的影响。因此，本研究旨在鉴定具有新生变异的潜在新型CAKUT疾病基因。方法：对209个CAKUT家族进行三基外显子组测序（ES），检测新的候选疾病基因。结果：在209个三重奏家族中，有96个家族的候选基因通过三重奏分析得到，占45.93%。在209例病例中的41例中，我们检测到45个潜在的新型CAKUT候选基因（19.62%）的强新生变异。我们开发了一种优先排序方法，强调SOX13 （HGNC:11192）的截断新生变异是CAKUT的一个有希望的原因。此外，我们还发现候选基因CHD1L （HGNC:1916）的等位基因携带者，从而支持CHD1L在CAKUT发病机制中的作用。结论：我们得出结论，潜在的新型CAKUT候选基因的新生变异有助于疾病病因学，并提出SOX13是CAKUT的潜在新病因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genetics in Medicine 医学-遗传学

CiteScore

15.20

自引率

6.80%

发文量

857

审稿时长

1.3 weeks

期刊介绍： Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health. GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.