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Am J Med Genet A. 2017 May 17. doi: 10.1002/ajmg.a.38274. [Epub ahead of print]

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

Author information

1
Department of Orthodontics and Craniofacial Biology, Radboud university medical center, Nijmegen, The Netherlands.
2
Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
3
Centre for Molecular and Biomolecular Informatics, Radboud university medical center, Nijmegen, The Netherlands.
4
Department of Pediatric Haematology and Oncology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
5
Université Catholique de Louvain, Cliniques Universitaires St Luc, Service de Gastroentérologie et Hépatologie Pédiatrique, Brussels, Belgium.
6
Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
7
Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
8
Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.

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.

KEYWORDS:

AEC; Bartsocas-Papas syndrome; CHUK; EEC; cocoon syndrome; ectodermal dysplasia

PMID:
28513979
DOI:
10.1002/ajmg.a.38274

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