Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CHUK

Green List (high evidence)

Comment on list classification: Sufficient peer-reviewed human and functional evidence supports promotion to Green in the next panel update. The association comprises >3 unrelated affected individuals, with consistent biallelic inheritance, overlapping immunodeficiency phenotypes and functional evidence of disrupted IKKα signalling.

Created: 30 Oct 2026, 12:57 p.m. | Last Modified: 30 Oct 2026, 12:57 p.m.

Panel Version: 9.112

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 biallelic CHUK kinase deficiency causes syndromic immunodeficiency and immune dysregulation and is compatible with life, whereas complete protein loss/ loss of function is associated with severe phenotypes cited above.

Multiple affected individuals with kinase-disrupting variants from five unrelated families with relevant immunodeficiency phenotypes have been reported, with functional evidence supporting both variant-level pathogenicity and disease mechanism:

(1) PMID 29523099, compound-heterozygous CHUK c.1365del (p.Arg457AspfsTer6)/c.1388C>A (p.Thr463Lys), with recurrent bacterial and viral infections and mild immune dysfunction as per laboratory measurements; interpretation is confounded by a concurrent approximately 2-Mb 1q21.1–q21.2 deletion.
(2) PMID 34533979, homozygous p.Tyr580Cys, with recurrent infections, hypogammaglobulinaemia, reduced B-cell numbers and absent secondary lymphoid structures; whilst intrinsic kinase activity was retained, functional studies demonstrated disrupted NIK binding and NF-KB2 p100 processing, and homozygous knock-in mouse recapitulated immune abnormalities seen in human subjects.
(3) PMID 39550372, exome sequencing identified three affected individuals from two unrelated families homozygous for c.499G>A (p.Gly167Arg), with recurrent infections and hypogammaglobulinaemia, and chronic diarrhea; functional studies showed the variant preserved IKKα expression but abolished kinase activity leading to impaired activation of the non-canonical NF-KB pathway.
(4) PMID 39812688, 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.

Additional supporting evidence from Ikkα-deficient haematopoietic chimeras and phosphorylation-deficient Ikkα^AA^ mice demonstrated impaired B-cell maturation, secondary lymphoid-organ formation and impaired processing of NF-KB2/p100, an effector of the non-canonical NF-κB pathway, thus supporting disruption of non-canonical NF-KB signalling as the disease mechanism (PMID: 11520989).

N.B. gene aliases include IKK-alpha, IKKA.

Created: 30 Oct 2026, 12:55 p.m. | Last Modified: 30 Oct 2026, 12:55 p.m.

Panel Version: 9.111

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Immune system disorder (MONDO:0005046); immunodeficiency disease (MONDO:0021094)

Publications

• 29523099
• 34533979
• 39550372
• 39812688
• 11520989

Comment on list classification: New gene added by Inga Nartisa. Biallelic variants are typically associated with Cocoon syndrome (MIM# 613630; definitive in G2P) or Popliteal pterygium syndrome (MIM# 619339), but immune deficits are not known to be associated. Only a single patient with a history of recurrent pneumonias and failure to thrive identified to date with a homozygous variant in this gene (PMID: 34533979). Therefore, rating Red for now, awaiting further cases/reports that corroborate this association.

Created: 17 May 2023, 2:09 p.m. | Last Modified: 17 May 2023, 2:09 p.m.

Panel Version: 4.12

Green List (high evidence)

Sources: Expert Review, Literature

Created: 29 Nov 2022, 9:03 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
recurrent infections; skeletal abnormalities; absent secondary lymphoid structures; reduced B cell numbers; hypogammaglobulinemia; lymphocytic infiltration of intestine and liver

Publications

• PMID: 35748970
• PMID: 34533979