STK4 was first reported in relation to autosomal recessive combined immunodeficiency in 2012 (Abdollahpour H, et al., 2012, PMID: 22294732; Nehme NT, et al., 2012, PMID: 22174160). Serine/threonine kinase 4 (STK4), encodes mammalian Sterile 20-like kinase 1 (MST1; distinct from the gene MST1 or macrophage stimulating 1) which is involved in cell death, following caspase-cleavage, it enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. It is a key component of the Hippo signaling pathway, which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. STK4 deficiency is characterized by a progressive loss of naive T cells, the consequences of which include recurrent bacterial and viral infections and autoimmune manifestations. Curated evidence supporting the gene-disease relationship includes 6 probands plus 6 additional affected family members, with biallelic loss of function (nonsense and frameshift) variants, reported in 5 publications (PMIDs: 22294732, 22174160, 22952854, 26117625, 26801501). Parents and healthy siblings were heterozygous for the mutation, consistent with autosomal recessive inheritance (PMID: 22294732), with no evidence of dominant disease by haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, including its enhanced expression in hematopoietic tissues (PMID: 22174160) and its function in apoptosis (PMID: 11278283), which is consistent with increased cell death of naive and proliferating T cells leading to lymphopenia in patients. This function is altered in patient cells (PMID: 22294732), which also have altered expression of Foxo1, Il7Rα, L-selectin, and CCR7, which can cause altered T-cell homing to secondary lymphoid organs (PMID: 22174160). Models have recapitulated the T lymphopenia with profound loss of naïve T cells in both knockout and cell-specific knockout mice (PMIDs: 19073936, 19692642). More evidence is available in the literature, but the maximum score was reached. In summary, STK4 is definitively associated with autosomal recessive combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date May 19, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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