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Novel NGLY1 gene variants in Chinese children with global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty

Journal of Human Genetics volume 65, pages 387–396 (2020)Cite this article

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Abstract

NGLY1 deficiency is the first and only autosomal recessive congenital disorder of N-linked deglycosylation (NGLY1-CDDG). To date, no patients with NGLY1 deficiency has been reported from mainland China or East Asia in English literature. Here, we present six patients with a diagnosis of NGLY1-CDDG on the basis of clinical phenotype, genetic testing, and functional studies. We retrospectively analyzed clinical phenotypes and NGLY1 genotypes of six cases from four families. Informed consent was obtained for diagnosis and treatment. In-silico tools and in vitro enzyme activity assays were used to determine pathogenicity of NGLY1 varaints. All patients had typical features of NGLY1-CDDG, including global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty. Dysmorphic features found in our patients include flat nasal bridge, loose and hollow cheeks, short stature, malnutrition, and ptosis. Pachylosis could be a novel cutaneous feature that may be explained by lack of sweat. We found three novel variants, including one missense (c.982C > G/p.Arg328Gly), one splice site (c.1003+3A > G), and one frame-shift (c.1637-1652delCATCTTTTGCTTATAT/p.Ser546PhefsTer) variant. All mutations were predicted to be disease causing with in-silico prediction tools, and affected at least one feature of gene splicing. Protein modeling showed missense variants may affect covalent bonding within the protein structure, or interrupt active/binding amino-acid residues. In vitro studies indicated that proteins carrying missense variants (p.Arg328Gly and p.Tyr342Cys) lost the enzyme activity. We expanded clinical phenotype and genetic mutation spectrum of NGLY1-CDDG by reporting six cases, three novel variants, and novel clinical features from mainland China.

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Funding

This work was supported by National Natural Science Foundation of China [81873543, and 81570468 to J.S.W.] and National Science and Technology Major Project [2014ZX09101046-004 to L.C.].

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Author notes

  1. These authors contributed equally: Kuerbanjiang Abuduxikuer, Lin Zou, Lei Wang

Authors and Affiliations

  1. Department of Hepatology, Children’s Hospital of Fudan University, 399 Wanyuan Road, 201102, Shanghai, China

    Kuerbanjiang Abuduxikuer & Jian-She Wang

  2. Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China

    Lin Zou, Lei Wang & Li Chen

Authors
  1. Kuerbanjiang Abuduxikuer
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  2. Lin Zou
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  4. Li Chen
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  5. Jian-She Wang
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Contributions

WJS and CL designed the study and approved the final submission; AK collected clinical and genetic data, performed protein modeling, conducted literature search, and summarized relevant information. Both WJS and AK clinically managed patients. ZL, WL, and CL performed functional studies. AK, ZL, and WL co-wrote the manuscript, and contributed equally for this study.

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Correspondence to Li Chen or Jian-She Wang.

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Abuduxikuer, K., Zou, L., Wang, L. et al. Novel NGLY1 gene variants in Chinese children with global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty. J Hum Genet 65, 387–396 (2020). https://doi.org/10.1038/s10038-019-0719-9

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