Cytopenia - NOT Fanconi anaemia

Gene: CASP10

I don't know

Comment on list classification: Despite sufficient cases being reported with the phenotype, the presence of identified variants in healthy individuals, reduced segregation of variants with the disease, inconsistencies in the reported phenotypes across cases with the same variants, and normal FAS-mediated apoptosis with variants from affected individuals suggest that this gene should not be promoted to green rating.

Created: 19 Jun 2025, 4:26 p.m. | Last Modified: 19 Jun 2025, 4:26 p.m.

Panel Version: 4.14

PMID:34329798 - Two patients were identified with heterozygous p.Ile406Leu variant and one was identified with p.Cys401LeufsTer15 variant. The p.Ile406Leu variant did not segregate with the disease, while the family of the patient with p.Cys401LeufsTer15 variant was not studied. The p.Ile406Leu variant, which was previously reported in several cases was found at an allele frequency of 2% in healthy individuals in certain ethnicities from the 1000 genomes database. In addition, functional assays did not show any impairment in one of these patients and five previously reported patients in comparison to healthy donors. Although p.Cys401LeufsTer15 variant was classified as likely pathogenic, it is also proposed that it is not per se causative of disease as the variant is present at higher than expected allele frequency in healthy individuals. There is also significant differences in the clinical presentations with the patient with this variant in this publication and a previously reported patient within the same variant. Another previously reported variant, p.Tyr446Cys was also present at an allele frequency of 4% in healthy individuals from 1000 genomes database, and p.Val410Ile was discarded as disease-causing by the same authors.

PMID:38704374 aimed to assess the impact of CASP10 variants on ALPS pathogenesis. Using a large cohort dataset, the authors were able to confirm that the missense variants p.Val410Ile and p.Tyr446Cys, are present in the general population at a high frequency. Furthermore, these variants do not affect the CASP10 catalytic domain and no difference was observed in CASP10 protein expression or FAS-mediated apoptosis between healthy controls and subjects bearing these variants in both homozygous and heterozygous states. Two patient had the CASP10 variant p.Cys401LeufsTer15, which lies within QACQG catalytic site in the CASP10 catalytic domain. One of the two patients was homozygous for this variant, resulting in a lack of Caspase-10 RNA and protein. However, it was reported that FAS-mediated apoptosis was comparable to healthy controls in each of the tested cell lines suspected to have a role in ALPS. In the other patient, who was heterozygous p.Cys401LeufsTer15, the authors report that although the levels of CASP10 protein expression was reduced, there was normal FAS-mediated apoptosis compared to healthy controls. From these results, it was concluded that Caspase-10 is dispensable for FAS-mediated apoptosis and an undetectable CASP10 protein expression has no impact on lymphocyte apoptosis and on individuals’ clinical and laboratory phenotype. It is also commented that post-translational or epigenetic mechanisms may play a role and yet unidentified.

Created: 19 Jun 2025, 4:20 p.m. | Last Modified: 19 Jun 2025, 4:20 p.m.

Panel Version: 4.9

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autoimmune lymphoproliferative syndrome, type II, OMIM:603909

Publications

• 34329798
• 38704374

Green List (high evidence)

CASP10 pathogenic variants (germline or somatic) causes ALPS, which has a complex phenotype including different cytopenias (mostly autoimmune).
Sources: Other

Created: 13 Oct 2024, 8:57 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
ALPS