CASP10 deficiency was first reported as the cause of autoimmune lymphoproliferative syndrome (ALPS) type 2A in 1999 (PMID: 10412980). Patients with this disorder present with hepatosplenomegaly, chronic non-infectious non-malignant lymphadenopathy and the development of autoimmune disorders, in particular anaemia, thrombocytopenia and neutropenia. Characteristic laboratory findings include an increased in double-negative (CD4-/CD8-) alpha/beta T-cells, hypergammaglobulinemia and impaired lymphocyte apoptosis.
Nine variants (missense and frameshift) have been reported in multiple probands in multiple publications (PMIDs: 10412980, 16446975, 31309545, 36844186, 17999750, 32599613, 27872624). Five of the nine variants (Ile406Leu, Val410Ile, Tyr466Cys, Leu522Ile, Pro501Leu) have subsequently shown to have high allele frequencies in the population not consistent with a monogenic disorder.
The mechanism of pathogenicity is proposed to be dominant-negative. Functional studies demonstrating a dominant-negative effect demonstrated the same results for a rare variant (Leu285Phe) and a common polymorphism (Ile406Leu), therefore the mechanism is not proven (PMID: 16446975). Many reported probands have unaffected parents with the same variant, so penetrance is proposed to be incomplete.
Expression studies, protein interaction studies and functional studies confirms the role of CASP10 in apoptosis. CASP10 is expressed in many tissues, including lymphoid organs and lymphocytes (Vincenz et al., 1997 and Wang et al., 2001). CASP10 is recruited to Fas and TNF receptor by FADD (Vincenz et. al, 1997), and is essential for FasL and TRAIL induced apoptosis (Wang et al., 2001) which are known to be defective in other forms of ALPS. Mutated CASP10, which lacks the active site, interferes with FasL and TRAIL induced apoptosis in transfected cells, supporting a dominant-negative model (Wang et al., 2001). Mice lack Casp10 and therefore a mouse model does not exist. Recently Magerus et al. asserted that biallelic mutations that completely abolish caspase-10 have no impact on FAS-induced apoptosis, however this data is not yet published.
In summary, there is limited evidence supporting the relationship between CASP10 and autosomal dominant autoimmune lymphoproliferative syndrome (ALPS) type 2A. This classification was approved by the ClinGen PIRD GCEP on the meeting date 19th March 2024 (SOP Version 10).
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