De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease

Genome Medicine
Shinichi TakahashiMichael Snyder

Abstract

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood. We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles. In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Bio...Continue Reading

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Citations

Jan 19, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jennifer E PoseyUNKNOWN Centers for Mendelian Genomics
Nov 14, 2019·International Journal of Molecular Sciences·Abdullah Hoter, Hassan Y Naim
Nov 18, 2018·Pediatric Research·Cindy BokobzaPierre Gressens
Oct 24, 2019·Cell Stress & Chaperones·Patrick A WilliamsTodd I Strochlic
Jun 10, 2021·NPJ Genomic Medicine·Esha Bhattacharjee, Arindam Maitra

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Methods Mentioned

BETA
exome sequencing
nucleotide exchange

Software Mentioned

SIFT
- 2
Burrows Aligner
Novoalign
mpileup
Clustal Omega
VCFtools
SKAT
PolyPhen
Phyre2

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