STK4 – Combined Immunodeficiency due to STK4 Deficiency

The association between STK4 loss-of-function variants and combined immunodeficiency due to STK4 deficiency is supported by multiple independent families manifesting an autosomal recessive inheritance pattern. The ClinGen classification for this gene–disease pair is Strong based on the accumulation of homozygous loss-of-function variants and robust functional concordance.

Homozygous variants segregate with disease across affected kindreds. In the initial family, two siblings harbored a homozygous c.442C>T (p.Arg148Ter) variant resulting in absent MST1 protein expression (PMID:26801501). Linkage analysis in the wider pedigree confirmed cosegregation with immunodeficiency in additional relatives (PMID:26801501).

To date, 5 probands across 4 unrelated families have been described with homozygous STK4 loss-of-function alleles, including c.442C>T (p.Arg148Ter), c.523dupA (p.Thr175AsnfsTer45), c.871C>T (p.Trp190Ter), and c.1311del (p.Ser438ValfsTer17) (PMID:26801501; PMID:33078349; PMID:34427831; PMID:38361950). Variants are exclusively protein-truncating, consistent with a null mechanism.

Functional analyses in patient lymphocytes reveal defective adhesion to ICAM-1 under shear stress, impaired chemotaxis toward CXCL11, and reduced phosphorylation of TBK1 and IRF3 leading to blunted type I–III interferon responses (PMID:26801501; PMID:33078349). These findings recapitulate murine Mst1 deficiency and support loss of MST1 kinase activity as the pathogenic mechanism.

A hypomorphic C-terminal SARAH domain frameshift variant (c.1311del (p.Ser438ValfsTer17)) yields truncated protein that evades nonsense-mediated decay and confers a milder clinical phenotype while retaining T-cell lymphopenia, highlighting allelic variability without refuting pathogenicity (PMID:38361950).

Collectively, genetic and experimental evidence meets ClinGen Strong criteria for autosomal recessive STK4-related combined immunodeficiency. Further studies may elucidate genotype–phenotype correlations and therapeutic targeting of Hippo pathway alterations. Key take-home: STK4 loss-of-function variants are diagnostic for combined immunodeficiency due to MST1 deficiency and guide clinical management.

References

• Journal of clinical immunology • 2016 • Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency PMID:26801501
• Journal of clinical immunology • 2021 • STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling PMID:33078349
• Journal of clinical immunology • 2021 • A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes PMID:34427831
• Frontiers in immunology • 2024 • A unique STK4 mutation truncating only the C-terminal SARAH domain results in a mild clinical phenotype despite severe T cell lymphopenia: Case report. PMID:38361950

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