Submission Details

HYOU1 (also known as ORP150, HSP12A, and Grp170) was first reported in relation to autosomal recessive granulocytopenia with immunoglobulin abnormality in 2017 (Haapaniemi et al., PMID: 27913302). Immunodeficiency-59 and hypoglycemia (IMD59) is an autosomal recessive primary immunologic disorder characterized by combined immunodeficiency and recurrent septic infections of the respiratory tract, skin, and mucous membranes, as well as disturbed glucose metabolism. Granulocyte, B-cell, and dendritic cell deficiency are present.

Six missense variants reported in four probands in four publications (PMIDs: 27913302, 35549617, 35822684, 32888943) are included in this curation. The probands presented with frequent septic infections of the respiratory tract and skin, granulocytopenia, psychomotor deterioration, neutropenia, low B-cell count, normal CD4+ T cells, and normal CD8+ T cells among other phenotypes. The mechanism of pathogenicity is not clear. Other pathogenic or likely pathogenic variants reported in ClinVar are large copy number changes that include more genes than HYOU1.

This gene-disease relationship is also known as immunodeficiency 59 and hypoglycemia (MONDO:0009305) which has been supported by experimental evidence (expression studies) (PMIDs:18094145, 35822684). ORP150 plays an important role in protein folding and secretion in the ER, perhaps as a molecular chaperone in concert with other stress-induced genes referred to as glucose-regulated proteins (GRPs). GRPs are members of the stress-responsive superfamily of genes that also includes heat shock proteins (HSPs). GRPs and HSPs are essential for normal cellular function, and ORP150 regulation may play a crucial role in coping with environmental stress. HYOU1 is one of many genes that are associated with congenital neutropenia, disorders characterized by low neutrophil counts, susceptibility to infections, and viable developmental abnormalities. The hypogammaglobulinemia associated with HYOU1 deficiency is however less common among congenital neutropenia disorders. Like many of the other congenital neutropenia genes, pathogenic variants in HYOU1 are associated with a risk for leukemic transformation.

Animal models (PMIDs: 10037731, 15223375, 11714735) of ORP150 deficiency do not have signs of granulocytopenia or hypogammaglobulinemia but instead, exhibit neurodegenerative features. Neurodegeneration has not been described in patients with HYOU1-related granulocytopenia with immunoglobulin abnormality but most have died early in life so it remains unclear whether this could develop with age.

In summary, there is limited evidence supporting the relationship between HYOU1 and autosomal recessive granulocytopenia with immunoglobulin abnormality. This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on the meeting date January, 21, 2025 (SOP Version 11).