Submission Details

CHUK was first reported in relation to autosomal recessive inheritance in Cocoon syndrome in 2010 (Lahtela et al ., PMID: 20961246) and Popliteal pteryium syndrome, Bartoscas-Papas type 2 in 2015 (Leslie et al., PMID: 25691407). The first reporting of a CHUK variant with symptoms of hypogammaglobinemia was in 2017 (Khandelwal et al., PMID:28513979) however only one pathogenic variant was found. The second pathogenic variant was identified in the proband documented in a current pre-print article by Riller et al., (PMID: 38798321). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms and inheritance pattern; therefore, the following disease entities have been lumped into one disease entities, Cocoon syndrome (OMIM: 613630) and Popliteal pterygium syndrome, Bartoscas-Papas type 2 (OMIM: 619339).
Six variants (missense and frameshift) that have been reported in three probands in three publications (PMIDs: 29523099, 34533979, 38798321 - pre-print) are included in this curation. These probands have recurrent upper and lower respiratory infections and hypogammaglobulinemia as well as abnormal skeletal morphology. There are no documented phenotypes reported in carriers of these variants. The mechanism of pathogenicity appears to be loss of function

This gene-disease relationship is also supported by experimental evidence (animal models, expression studies, rescue, and in vitro functional assays,) (PMIDs: 29523099, 34533979, 38798321-pre-print). Expression studies and in vitro functional assays show that non-canonical NF-kB signaling is impaired through the disruption of NIK binding and lack of p100 processing. Expression studies from the pre-print, Riller et al., (2024) showcases that introduction of wildtype CHUK sequence is able to rescue p100 processing and increase nuclear translocation of RELB in transduced fibroblasts (PMID:38798321-pre-print). Animal models are able to capture proband phenotypes and showcase reduced mature B cells, a severe reduction in serum IgG and IgA levels, a reduction in memory and effector T cells, inability to respond to immunization, and recurrent infections.
In summary, there is moderate evidence supporting the relationship between CHUK and autosomal recessive Popliteal pteryium syndrome, Bartoscas-Papas type 2. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date June 7th, 2024 (SOP Version 10).