RET compound inheritance in Chinese patients with Hirschsprung disease: lack of penetrance from insufficient gene dysfunction

Abstract

Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of enteric ganglia along variable lengths of the intestine. Genetic defects play a major role in HSCR pathogenesis with nearly 50% of patients having a structural or regulatory deficiency in the major susceptibility gene RET. However, complete molecular defects remain poorly characterized in most patients. Here, we performed detailed genetic, molecular, and populational investigations of rare null mutations and modifiers at the RET locus. We first verified the pathogenicity of three RET splice site mutants (c.1879 + 1G > A, c.2607 + 5G > A and c.2608-3C > G) at the RNA level. We also identified significantly higher risk allele (genotype) frequencies, and their over-transmission, from unaffected parents to affected offspring of three functionally independent enhancer variants (rs2506030, rs7069590 and rs2435357, with odd ratios (OR) of 2.09, 2.71 and 7.59, respectively, P < 0.001). These three common variants are in significant (P < 4.64 × 10–186) linkage disequilibrium in the Han Chinese population with ~ 60% of them carrying at least one copy and > 10% with two copies. We show that RET compound inheritance of rare and common variants prevails in 64% (seven out of 11) of Chinese HSCR families. This study supports the idea that common RET variants can modify the penetrance of rare null RET mutations in HSCR, and the combined high susceptibility allele dosage may constitute the unique raised “risk baseline” among the Chinese population.

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Data availability

The raw WES data are not publicly available due to privacy or ethical restrictions. Processed genetic data generated or analyzed within this study are available upon request.

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Acknowledgements

We are grateful to the many patients and their families whose cooperation made this study possible. The English language editing was achieved at American Journal Experts. We also thank Prof. Aravinda Chakravarti from the New York University School of Medicine and Dr. Sen Zhao, Nan Wu from the Peking Union Medical College Hospital for comments on this manuscript.

Funding

This work was made possible by a grant from the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-I2M) and the National Natural Science Foundation of China (81771620, 82070532) to Qian Jiang. Yang Wang was supported by the National Natural Science Foundation of China (81670469), Shanghai Municipal Commission of Health and Family Planning (201840028) and the Innovative Research Team of High-level Local Universities in Shanghai. Zhen Zhang was supported by the National Natural Science Foundation of China (81700451). Shuhua Xu was supported by the National Natural Science Foundation of China (91731303, 31771388, 31961130380, and 31711530221), the National Science Fund for Distinguished Young Scholars (31525014), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). Wei Cai was supported by the National Natural Science Foundation of China (81630039) and Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition (17DZ2272000). Long Li was supported by grants from the Public Welfare Industry Research Special Foundation of China (201402007).

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QJ and YW prepared the manuscript. QJ and YW performed the genetic analyses and minigene study. HW, QL and ZZ conducted sample acquisition and collected clinical information. YG and SX conducted haplotype frequency analyses in the Han Chinese population. WC and LL supervised the study and edited the manuscript.

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Correspondence to Wei Cai or Long Li.

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Patient sampling was conducted through the Hirschsprung Disease Consortium of China (HDCC) spanning two clinical centers across North and South China. This study was approved by the medical ethics committee of the Capital Institute of Pediatrics (SHERLL 2013039) and Xinhua Hospital (XHEC-C-2016-263) and was carried out according to the Declaration of Helsinki.

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Jiang, Q., Wang, Y., Gao, Y. et al. RET compound inheritance in Chinese patients with Hirschsprung disease: lack of penetrance from insufficient gene dysfunction. Hum Genet (2021). https://doi.org/10.1007/s00439-020-02247-y

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