Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations


Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein–Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.

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Data Availability

The data that support the findings of this study are available upon request from the corresponding author. The genetic data are not publicly available due to data privacy or ethical restrictions.


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The authors would like to thank the patients and their families for participating in this study.


Research in CP laboratory was supported by the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH) and ERA-Net for Research Programmes on Rare Diseases (E-Rare: EuroCID, ANR RANR187; n°061-2016-050). Research in EVS laboratory was supported by Euroglycan-omics (E-RARE 18-117) through a grant from the FNRS.

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MF and AV analyzed the genetics and clinical data and wrote the manuscript. JR and EL interpreted the genetics. MVDC, TK, and EVS performed and analyzed the enzymatic experiments. CFB, ALD, NS, and VCD provided their expertise on skeletal dysplasia and congenital disorders of glycosylation. MC, BF, JS, LR, FMP, AN, BN, and DM took care of the patients and provided clinical data. SB and CP analyzed the genetic data and designed the study. All authors critically reviewed the manuscript.

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Correspondence to Mathieu Fusaro.

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Fusaro, M., Vincent, A., Castelle, M. et al. Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations. J Clin Immunol (2021).

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  • Phosphoglucomutase 3
  • PGM3
  • N-Acetylphosphoglucosamine
  • Congenital disorders of glycosylation
  • Severe combined immunodeficiency
  • Primary immunodeficiency
  • Skeletal dysplasia