Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome‐like phenotype and hypogammaglobulinemia

Abstract

The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here.

Atrial fibrillation in a pediatric patient caused by an unusual malignant etiology: A case report

“…An added feature of note in this case is that during infancy, she was diagnosed with a Hay-Wells syndrome-like phenotype (15). The ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome or Hay-Wells syndrome (MIM #106260) was first reported in 1976 (16).…”

“…The variant in CHUK appeared to be most relevant for the AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation (15).…”

Exploiting gene dependency to inform drug development for multiple myeloma

“…RNA interference screening has previously identified CHUK as a lenalidomide sensitiser in MM 29 . CHUK encodes a component of the IKK complex that plays a key role in NF-κB pathway activation 30 . IKBKB is currently undergoing investigation as a therapeutic target in pancreatic carcinoma, lymphoid neoplasms and melanoma (Supplementary Table 6 ).…”

Skin manifestations of inborn errors of NF-κB

“…Another child was reported with Bartocas-Papas syndrome, including alopecia totalis, microphthalmia, ankyloblepharon, cleft palate and popliteal webs ( 87 ) ( Table 3 ). Another case arising from heterozygous de novo CHUK mutations was identified in a patient with ankyloblepharon-ectodermal defects-cleft lip/palate (AEC syndrome), as well as buccal synechiae, hypoplastic thumbs and 3rd-5th toe syndactyly ( 88 ). Ectodermal defects included sparse hair, conical teeth and nail defects.…”