Autoinflammatory Disorders

Gene: DPP9

Green List (high evidence)

3 unrelated families and supporting null mouse model. IUIS IEI committee assign the condition to diseases of immune dysregulation in the subcategory of Familial Hemophagocytic Lymphohistiocytosis (FHL syndromes).
Sources: Expert Review

Created: 16 Nov 2024, 2:30 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
hatipoglu immunodeficiency syndrome MONDO:0957229

Publications

• 36112693

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Three families (four children) with immune-associated defects, poor growth, pancytopenia and skin pigmentation abnormalities that segregate with biallelic DPP9 rare variants.

Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hylomorphic or knockout alleles that failed to repress NLRP1. Experiments suggested that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome.

Recessive loss of function DPP9 germline variants found in three families.

c.2551C>T; p.(Gln851*) homozygous in child and het in parents.
c.449G>A; p.(Gly167Ser)/c.641C>G; p.(Ser214*) comp het child, proven in trans.
c.331C>T; p.(Arg111*) homozygous in one child and two cousins (consanguineous family).

All four children shared a triad of symptoms which were termed “Hatipoglu syndrome”. These included failure to thrive, skin manifestations, pancytopenia and susceptibility to infections. This Mendelian disease bears some degree of resemblance with auto-immune disorders caused by NLRP1 activating mutations.

Created: 4 May 2023, 2:26 a.m. | Last Modified: 4 May 2023, 2:26 a.m.

Panel Version: 1.4

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hatipoglu immunodeficiency syndrome MIM#620331

Publications

• 36112693

Green List (high evidence)

Amber for mono-allelic association:

de novo monoallelic dominant-negative mutation in DPP9 (c.755G>C, R252P) presenting with HLH at ~2m. Functional data supporting dominant negative mechanism.

Created: 8 Aug 2023, 6:32 a.m. | Last Modified: 8 Aug 2023, 6:32 a.m.

Panel Version: 1.1095

Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopenias.
Sources: Expert Review

Created: 22 Sep 2022, 8:42 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias

Publications

• 36112693
• 37544411

Green List (high evidence)

de novo monoallelic dominant-negative mutation in DPP9 (c.755G>C, R252P) presenting with HLH at ~2m. Functional data supporting dominant negative mechanism.

Created: 7 Aug 2023, 11:39 p.m. | Last Modified: 7 Aug 2023, 11:39 p.m.

Panel Version: 1.9

Three unrelated families with Hatipoğlu syndrome with biochemical and cellular assays, mouse and zebrafish models. Immunological features of recurrent fevers, repeated infections, herpes susceptibility, cytopaenias.
Sources: Literature

Created: 19 Sep 2022, 10 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
HLH

Publications

• PMID: 37544411