Limb disorders

Gene: CHUK

Green List (high evidence)

CHUK is provisionally associated with autosomal recessive Cocoon syndrome (OMIM#613630) and autosomal; recessive Popliteal pterygium syndrome, Bartsocas-Papas type 2 (OMIM#619339).

Evidence suggests that biallelic CHUK kinase deficiency causes syndromic immunodeficiency and immune dysregulation compatible with life, whereas complete loss of IKKα function is associated with severe polymalformation phenotypes. Multiple affected individuals with loss-of-function or specifically kinase-disrupting variants have been reported with relevant syndromic immunodeficiency phenotypes, with functional evidence supporting both variant pathogenicity and the disease mechanism. Three affected individuals also had developmental limb abnormalities and orofacial clefting, features recapitulated in IKKα-deficient mouse models.

Leslie et al., 2015 (PMID 25691407) reported a homozygous variant in the splice acceptor site of exon 10 (c.934-2A > G) in a female patient with Bartsocas-Papas syndrome with a severe multi-systemic phenotype including syndactyly and orofacial clefting. IKKα null mice die at birth with cleft secondary palate, failed epidermal keratinization, hypoplastic limbs, and other skeletal abnormalities (Li et al., 1999, PMID 10346820).

Riller et al. 2025 (PMID 39812688) reported compound-heterozygous c.425A>G (p.His142Arg)/c.569C>T (p.Pro190Leu), in a female proband with infantile hypogammaglobulinaemia, recurrent respiratory infections and immune dysregulation; both variants impaired IKKa kinase function, and introducing wild-type CHUK rescued restored non-canonical NF-KB activation. The proband also presented with a polymalformative phenotype, which included ectrodactyly of the feet, hypoplasia of both thumbs, and cleft palate.

Cadieux-Dion et al. 2018 (PMID 29523099) reported compound-heterozygous CHUK c.1365del (p.Arg457AspfsTer6)/c.1388C>A (p.Thr463Lys), with recurrent bacterial and viral infections and mild immune dysfunction, in addition to cleft lip/ palate, clinodactyly and syndactyly, without additional notable skeletal features; the patient also harbored an approximately 2-Mb 1q21.1–q21.2 deletion.

Bainter et al. 2021 (PMID 34533979) reported homozygous p.Tyr580Cys in a patient with combined immunodeficiency and skeletal abnormalities, including defective sternal and sacral ossification/fusion; knock-in mice recapitulated the immune phenotype and showed defective rib fusion.

Cildir et al. 2024 (PMID 39550372) reported individuals with biallelic missense IKKα kinase-disrupting variants and a predominantly immunological phenotype, without skeletal or morphogenic abnormalities. Supporting phosphorylation-deficient IKKα mouse models similarly demonstrated abnormal immune development and non-canonical NF-κB signalling, without morphogenic abnormalities (Senftleben et al. (PMID 11520989)).

N.B. gene aliases include IKK-alpha, IKKA.
Sources: Literature

Created: 12 Nov 2026, 1:41 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Popliteal pterygium syndrome, Bartsocas-Papas type 2, OMIM:619339; Bartsocas-Papas syndrome 2, MONDO:0859154; Cocoon syndrome, OMIM:613630; AEC-like syndrome

Publications

• 25691407
• 10346820
• 39812688
• 29523099
• 34533979
• 39550372
• 11520989