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

Abstract

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.

Genetic susceptibility for celiac disease is highly prevalent in the Saudi population

“…Genome-wide association studies have identified a large number of non-HLA genes associated with CD, such as those coding for cytokines, chemokines and their receptors, cell adhesion molecules, and T- and B-cell activators. [ 32 33 34 35 36 ] The high consanguineous marriage rate in the Saudi community (40–60%)[ 6 37 ] and the clustering of CD cases in certain families are important reasons to conduct genome-wide association studies in Saudi Arabia. These studies would enhance the identification of new non-HLA genetic loci, which could shed light on new genes and genetic pathways involved in disease pathogenesis, and the possibility of a monogenic-form of CD could be explored.…”

Exploring celiac disease candidate pathways by global gene expression profiling and gene network cluster analysis

“…The genetic etiology of CeD is so far widely studied by different genetic approaches like candidate gene sequencing, exome sequencing, SNP genotyping and epigenetic screening 16,[19][20][21][22] . However, compared to the above-mentioned genotyping approaches, there are very few gene expression studies which have assessed the contribution of genes to the pathophysiology of CeD.…”

Familial/inherited cancer syndrome: a focus on the highly consanguineous Arab population

“…41 Studies investigating cancer susceptibility within families have suggested genetic links to an array of malignancies at the population level. 14,[142][143][144] Genetic screening offers increased monitoring and surveillance of those with a risk of cancer, in addition to prophylactic, risk-reducing interventions. 144 Fifteen relevant guidelines were developed to provide recommendations on genetic counselling (Supplementary Material) and were in general agreement of the importance of genetic counselling prior to BRCA testing, including breast cancer riskreduction procedures including mastectomy and oophorectomy.…”

“…Advances in sequencing technologies, particularly, high throughput sequencing have permitted the discovery of novel genes responsible for cancer heritability, facilitating efficient genetic screening. [14][15][16] The major genetic changes in cancer include single nucleotide variants (SNVs); duplications, insertions, or deletions; exon and gene copy number changes; and structural variants (SVs). 17 The molecular profiling of heritable cancer genes ranges from simple assessments of known hotspot mutations in single genes, to more complex tests that simultaneously detect all gene alterations using allele-specific PCR, Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), pyrosequencing or mass spectrometry (MS).…”

“…20,21 Accordingly, increased public awareness that cancer can be heritable, and that the heritable risk can be evaluated has increased as has the demand for genetic counselling and screening. 14,[22][23][24] The incidence and prevalence of hereditary cancer amongst different ethnic populations is often distinct. Cancer is a major problem in the Arab world 4,[25][26][27][28][29][30][31] which is delimited by Lebanon and Syria to the north, Morocco to the west, south to Yemen, and Iraq in the east, accounting for >300 million people.…”