Characteristics of Pediatric Crohn’s Disease in Saudi Children: A Multicenter National Study

Background and Aims. Crohn’s disease (CD) is an evolving disease in KSA. Little is known about its characteristics in the Saudi population. The aims of this study were to describe the characteristics of Saudi children with CD and to determine whether the characteristics of CD in KSA are different from those seen in Western countries. Methods. In this study, children younger than eighteen years of age diagnosed with CD between January 2003 and December 2012 were included. Results. Of 330 patients identified, 186 (56.4%) were males. The median age at diagnosis was 15.8 years. A positive family history for IBD in first-degree relatives occurred in 13.6% of patients. The most common symptoms were abdominal pain (84.2%), weight loss (75.2%), and diarrhea (71.8%). The main disease location was ileocolonic (42.1%) and the main disease behavior was nonstricturing and nonpenetrating (63.6%). Perianal involvement was seen in 60 (18.2%) patients. Laboratory findings revealed anemia in 57.9% of patients, low albumin in 34.5%, and high CRP in 39.4%. Conclusions. Saudi children with CD have lower frequency of first-degree relatives with IBD, lower prevalence of early onset disease, longer diagnostic delay, higher prevalence of growth failure, and greater frequency of stricturing and penetrating disease behavior compared to Western patients

Whole exome sequencing of a consanguineous family identifies the possible modifying effect of a globally rare AK5 allelic variant in celiac disease development among Saudi patients.

Celiac disease (CD), a multi-factorial auto-inflammatory disease of the small intestine, is known to occur in both sporadic and familial forms. Together HLA and Non-HLA genes can explain up to 50% of CD's heritability. In order to discover the missing heritability due to rare variants, we have exome sequenced a consanguineous Saudi family presenting CD in an autosomal recessive (AR) pattern. We have identified a rare homozygous insertion c.1683_1684insATT, in the conserved coding region of AK5 gene that showed classical AR model segregation in this family. Sequence validation of 200 chromosomes each of sporadic CD cases and controls, revealed that this extremely rare (EXac MAF 0.000008) mutation is highly penetrant among general Saudi populations (MAF is 0.62). Genotype and allelic distribution analysis have indicated that this AK5 (c.1683_1684insATT) mutation is negatively selected among patient groups and positively selected in the control group, in whom it may modify the risk against CD development [p<0.002]. Our observation gains additional support from computational analysis which predicted that Iso561 insertion shifts the existing H-bonds between 400th and 556th amino acid residues lying near the functional domain of adenylate kinase. This shuffling of amino acids and their H-bond interactions is likely to disturb the secondary structure orientation of the polypeptide and induces the gain-of-function in nucleoside phosphate kinase activity of AK5, which may eventually down-regulates the reactivity potential of CD4+ T-cells against gluten antigens. Our study underlines the need to have population-specific genome databases to avoid false leads and to identify true candidate causal genes for the familial form of celiac disease

Molecular view of wildtype (Red in color) and mutant (Yellow in color) AK5: a) Hydrophobic bonds arrangement in AK5-wildtype residues Iso561 with Iso556 and Ala557 and b) AK5-mutant residues Iso562 and Phe563.

<p>Molecular view of wildtype (Red in color) and mutant (Yellow in color) AK5: a) Hydrophobic bonds arrangement in AK5-wildtype residues Iso561 with Iso556 and Ala557 and b) AK5-mutant residues Iso562 and Phe563.</p

Whole exome sequencing of a consanguineous family identifies the possible modifying effect of a globally rare <i>AK5</i> allelic variant in celiac disease development among Saudi patients - Fig 3

<p>(A) Nucleotide sequence Alignment of human and primate adenylate kinase 5 genes. (B) Phylogenetic tree of the human adenylate kinases.</p

The genetic variants yield of a celiac disease family.

<p>The genetic variants yield of a celiac disease family.</p

List of nucleotide variants from exome data which showed autosomal recessive inheritance model in consanguineous celiac disease family.

<p>List of nucleotide variants from exome data which showed autosomal recessive inheritance model in consanguineous celiac disease family.</p

Chromosomal location of human <i>AK5</i> gene at 1p31.1 and chromatograms of ATT insertion sequence (wild type, heterozygote, and homozygous mutant genotypes) observed in celiac patients.

<p>(Chromosome and gene location figure generated from Ensembl browser).</p

Genotype and allelic distribution of <i>AK5</i>,c.1683_1684insATT variant between celiac sporadic patients and controls, as well as their risk prediction for celiac disease.

<p>Genotype and allelic distribution of <i>AK5</i>,c.1683_1684insATT variant between celiac sporadic patients and controls, as well as their risk prediction for celiac disease.</p