Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: PTPN6

Green List (high evidence)

Conference presentation CIS 2026 (https://doi.org/10.70962/cis2026abstract.18)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other

Created: 17 Jun 2026, 2:09 p.m. | Last Modified: 17 Jun 2026, 2:13 p.m.

Panel Version: 9.9

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoimmune cytopenias; hemolytic anemia; interstitial lung disease