A Novel De Novo Pgm3 Pathogenic Mutation Identified In An Infant Presenting With Abnormal Trec Assay And Severe Neutropenia

Phosphoglucomutase 3 (PGM3) deficiency is an autosomal recessive congenital glycosylation disorder associated with a variable clinical phenotype including immunodeficiency, atopy and progressive bone marrow failure. We present an infant with compound heterozygous pathogenic PGM3 mutations, including a novel de novo variant, who initially presented with an abnormal T-cell receptor excision circles (TREC) assay on newborn screen. Rapid whole genome sequencing was performed by Perkin Elmer Genomics on Illumina next generation sequencing system. A term Hispanic female born to non-consanguineous parents presented at two weeks of life for evaluation of abnormal TREC assay on newborn screen. Flow cytometry showed severe lymphopenia with decreased numbers of CD3+ T cells (305 cells/microL) and CD19+ B cells (398 cells/microL), and low percentage of naïve CD45RA+ T cells (18%, normal 64-95%). Proliferative responses to PHA mitogens were decreased. IgM and IgA were below the limit of detection but IgE was normal for age. The patient also had severe neutropenia (100-300 cells/microL) poorly responsive to filgrastim. Targeted sequencing of 25 genes associated with severe combined immunodeficiency revealed no pathogenic variants. Rapid whole genome sequencing showed two pathogenic variants in PGM3: a maternally inherited c.1049T>C (p.Ile350Thr) missense variant and a novel de novo c.1558C>T (p.Arg520Ter) nonsense variant. The patient underwent mismatched unrelated umbilical cord transplant with successful engraftment and no complications one month post-transplant. We present an infant with a novel pathogenic PGM3 mutation who presented with cellular immune deficiency and severe neutropenia. PGM3 deficiency should be considered for infants with abnormal TREC assay and neutropenia.