Genetic Spectrum of Congenital Anomalies of the Kidney and Urinary Tract in Chinese Newborn Genome Project

Zhelan Huang; Qian Shen; Bingbing Wu; Huijun Wang; Xinran Dong; Yulan Lu; Guoqiang Cheng; Laishuan Wang; Wei Lu; Liping Chen; Wenqing Kang; Long Li; Xinnian Pan; Qiufen Wei; Deyi Zhuang; Dongmei Chen; Zhaoqing Yin; Ling Yang; Qi Ni; Renchao Liu; Gang Li; Ping Zhang; Yanyan Qian; Xiaomin Peng; Yao Wang; Yun Cao; Hong Xu; Liyuan Hu; Lin Yang; Wenhao Zhou

doi:10.1016/j.ekir.2023.08.005

Genetic Spectrum of Congenital Anomalies of the Kidney and Urinary Tract in Chinese Newborn Genome Project

Kidney Int Rep. 2023 Aug 14;8(11):2376-2384. doi: 10.1016/j.ekir.2023.08.005. eCollection 2023 Nov.

Authors

Zhelan Huang¹, Qian Shen², Bingbing Wu¹, Huijun Wang¹, Xinran Dong¹, Yulan Lu¹, Guoqiang Cheng³, Laishuan Wang^{3

4}, Wei Lu⁵, Liping Chen⁶, Wenqing Kang⁷, Long Li⁸, Xinnian Pan⁹, Qiufen Wei⁹, Deyi Zhuang¹⁰, Dongmei Chen¹¹, Zhaoqing Yin¹², Ling Yang¹³, Qi Ni¹, Renchao Liu¹, Gang Li¹, Ping Zhang¹, Yanyan Qian¹, Xiaomin Peng¹, Yao Wang¹, Yun Cao^{3

4}, Hong Xu², Liyuan Hu^{3

4}, Lin Yang⁵, Wenhao Zhou^{1

3

4

10}

Affiliations

¹ Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.
² Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.
³ Division of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
⁴ Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
⁵ Department of Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China.
⁶ Jiangxi Provincial Children's Hospital, Nanchang, China.
⁷ Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
⁸ Department of Neonatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
⁹ Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
¹⁰ Xiamen Children's Hospital, Xiamen, China.
¹¹ Quanzhou Women and Children's Hospital, Quanzhou, China.
¹² The People's Hospital of Dehong, Dehong, China.
¹³ Hainan Women and Children's Medical Center, Haikou, China.

Abstract

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) corresponds to a spectrum of defects. Several large-cohort studies have used high-throughput sequencing to investigate the genetic risk of CAKUT during antenatal, childhood, and adulthood period. However, our knowledge of newborns with CAKUT is limited.

Methods: This multicenter retrospective cohort study explored the genetic spectrum of CAKUT in a Chinese neonatal cohort. Clinical data and whole exome sequencing (WES) data of 330 newborns clinically diagnosed with CAKUT were collected. WES data were analyzed for putative deleterious single nucleotide variants (SNVs) and potential disease-associated copy number variants (CNVs).

Results: In this study, pathogenic variants were identified in 61 newborns (18.5%, 61/330), including 35 patients (57.4%) with SNVs, 25 patients (41%) with CNVs, and 1 patient with both an SNV and a CNV. Genetic diagnosis rates were significantly higher in patients with extrarenal manifestations (P＜0.001), especially in those with cardiovascular malformations (P＜0.05). SNVs in genes related to syndromic disorders (CAKUT with extrarenal manifestations) were common, affecting 20 patients (57.1%, 20/35). KMT2D was the most common gene (5 patients) and 17q12 deletion was the most common CNV (4 patients). Patient 110 was detected with both a CNV (17q12 deletion) and an SNV (a homozygous variant of SLC25A13). Among the newborns with positive genetic results, 22 (36.1%, 22/61) patients may benefit from a molecular diagnosis and change in clinical management (including early multidisciplinary treatment, disease-specific follow-up, and familial genetic counseling).

Conclusion: This study shows the heterogeneous genetic etiologies in a Chinese CAKUT neonatal cohort by using WES. Patients with CAKUT who have extrarenal manifestations are more likely to harbor genetic diagnoses. Kabuki syndrome and 17q12 deletion syndrome were the most common genetic findings. Approximately 36.1% of the patients may benefit from molecular diagnoses and a change in clinical management.

Keywords: congenital anomalies of the kidney and urinary tract; genetic spectrum; infancy; kidney malformation; newborn; whole exome sequencing.