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. 2016 Oct 24;10(1):34.
doi: 10.1186/s40246-016-0091-1.

Novel Genetic Risk Variants for Pediatric Celiac Disease

Free PMC article

Novel Genetic Risk Variants for Pediatric Celiac Disease

Angeliki Balasopoulou et al. Hum Genomics. .
Free PMC article


Background: Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic.

Methods: Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition.

Results: Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population (P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance.

Conclusions: The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.

Keywords: Celiac disease; Disease predisposition; Family genomics; Genomic variants; Next-generation sequencing.


Fig. 1
Fig. 1
Distribution of newly identified risk variants in Greek and Serbian populations. a HoxD12 c.418G>A is more abundant in pediatric celiac disease patients of Greek and Serbian descent, reaching statistical significance (**P < 0.01) in the Serbian population. b NCK2 c.745_746delAAinsG is more abundant in healthy individuals of Greek and Serbian descent, reaching statistical significance (*P = 0.03) in the Greek population
Fig. 2
Fig. 2
a View of the SH3-3/LIM4 binding interface as previously shown by NMR spectroscopy [26]. The Nck2 DH3 domain interface is shown in gray and the PINCH-1 LIM4 domain in green. K249 interacts with E233 and is part of a network connecting R192 of LIM4 and N250 of SH3. b Structural model of the mutant p.K249E and the potential effect in the interactions between SH3 and LIM4

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