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A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants

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Abstract

Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant.

Conclusions: Our study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant.

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Availability of data and materials

The data supporting the findings of this study are available within the article and supplement. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors offer their sincere thanks to all the participants and their families.

Funding

This work was sponsored by Natural Science Foundation of Fujian Province (No. 2020J01125), the Key Clinical Special Discipline Construction Program of Fuzhou, Fujian, P.R.C (No. 201610191) and the Key Clinical Special Discipline Construction Program of Fujian Province.

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Authors and Affiliations

  1. Department of Endocrinology, Genetics and Metabolism, Fuzhou Children’s Hospital of Fujian Medical University, Fuzhou, 350000, China

    Huakun Shangguan, Jinduan Lin, Xiaozhen Huang, Yan Zeng & Ruimin Chen

  2. Department of Medical Genetics, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, Shanghai, 200127, China

    Jian Wang

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  1. Huakun Shangguan
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  2. Jian Wang
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Contributions

HS conducted the data analysis and interpretation and wrote the manuscript. JW and RC contributed to the study design and helped to analyze data and revise the first draft. JL, XH, and YZ assisted in collecting clinical information and data curation. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ruimin Chen.

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Ethics approval and consent to participate

This study was conducted in line with the principles of Helsinki Declaration and was approved by the Ethics Committee of Fuzhou Children’s Hospital of Fujian province. The authors affirm that human research participants provided informed consent for publication of the images in SFig. 1–1, 1–2, and 1–3.

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The authors declare no competing interests.

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Communicated by Peter de Winter

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Shangguan, H., Wang, J., Lin, J. et al. A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants. Eur J Pediatr 183, 1403–1414 (2024). https://doi.org/10.1007/s00431-023-05385-3

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