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

PloS One
Jumana Yousuf Al-AamaOmar I Saadah

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 aden...Continue Reading

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Citations

Jan 4, 2020·Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association·Norah D Al NofaieOmar I Saadah
Feb 7, 2020·NPJ Genomic Medicine·Fawz S AlHarthiMalak Abedalthagafi
Feb 3, 2021·NPJ Genomic Medicine·Fawz S AlHarthiMalak Abedalthagafi

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Methods Mentioned

BETA
biopsies
exome sequencing
biopsy
electrophoresis
PCR
genotyping

Software Mentioned

GraphPad
Pymol
NOMAD
ANNOVAR
GraphPad QuickCalcs
PRIMER3
Ensembl browser
PolyPhen
BLAST
Ref Server

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