6 research outputs found
Genome Sequencing of Idiopathic Pulmonary Fibrosis in Conjunction with a Medical School Human Anatomy Course
<div><p>Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF <i>per se</i>. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The <i>MUC5B</i> promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to <i>MUC5B</i>, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with <i>MUC5B</i> dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.</p></div
Variants associated with IPF that were also seen in this individual. Allele frequencies accessed 4/16/2014.
A<p>Discovery and <sup>B</sup>replicate GWAS.</p><p>Variants associated with IPF that were also seen in this individual. Allele frequencies accessed 4/16/2014.</p
Genes previously associated with familial IPF.
<p>Genes previously associated with familial IPF.</p
Integrated Genomics Viewer (IGV) screenshot of the rs35705950 variant.
<p>Integrated Genomics Viewer (IGV) screenshot of the rs35705950 variant.</p
Sequencing coverage and variant distribution within the <i>MUC5B</i> locus.
<p>(<b>A</b>) Sequence coverage of the <i>MUC5B</i> gene. (<b>B</b>) Rare variants neighboring the <i>MUC5B</i> promoter variant rs35705950. Variant track is colored by allele frequency (blue: AF<2%, red: AF<5%, black: AF<10%). No other rare variants in this region overlap with putative transcription factor binding sites, consistent with the hypothesis that the rs35705950 is causative of <i>MUC5B</i> dysregulation. Plots were generated using the UCSC genome browser (<a href="http://www.genome.ucsc.edu" target="_blank">http://www.genome.ucsc.edu</a>).</p
Histological demonstration of the NSIP pattern of IPF in the patient's lungs. Microscopic examination of the lungs.
<p>(<b>A</b>) 40×; (<b>B</b>) 400×. Note uniform fibrotic thickening of the alveolar septae and type II pneumocyte hypertrophy. There was no histologic evidence of sarcoidosis, hypersensitivity pneumonitis, organizing pneumonia, or diffuse alveolar damage.</p