The genetics of human severe pediatric gastroensophageal reflux disease

Fen Ze Hu

doi:10.17918/00001470

We recognized that severe pediatric gastroesophageal reflux disease (GERD) is familial and follows an autosomal dominant pattern of inheritance. GER is the retrograde movement of stomach contents into the esophagus, and is a major etiological factor in respiratory diseases, and disorders of the ears, nose, and throat. Severe GERD affects approximately 2% of children, but it is currently under diagnosed. A subject population for mapping was obtained through the auspices of the Pediatric/Adolescent Gastroesophageal Reflux Association from which a group of multiplex families was ascertained. A genome-wide scan performed at a resolution of 8 centiMorgans (cM) identified a 16 cM GERD locus on chromosome 13q with a multifamily LOD > 4. Analyses of additional meioses, fine mapping studies, and the human genome sequence were used to reduce the locus to 6 megabases and increase the multifamily LOD > 7. A multi-pronged strategy including candidate gene analyses, high throughput DNA sequencing, and SNP-based association studies, was employed to positionally clone the GERD gene. Two candidate genes were excluded, one by locus refinement and one by sequence analysis. Bulk DNA sequence analyses were performed on the DNAs of five affecteds and one unaffected for all exons for all genes, hypothetical genes, and ESTs within the locus. We also sequenced the proximal 5[prime] region from several of these genes. This resulted in the generation of 3.6 million base pairs of sequence from which we identified 163 novel SNPs and INDELS (insertions/deletions). Interfamilial-genic-consistency and phasing studies ruled out all of these mutations as being causative. A subset of these SNPs was used for a pair of association studies in which we: (1) examined a series of cases and controls; and (2) performed transmission disequilibrium testing. Data from these studies pointed to two possible areas within the GERD I locus, however, at the resolution at which we performed the scan it is likely that the critical region was missed. A plan is presented for future studies in which a high density SNP scan would be performed across the entire locus to identify the causative gene using Illumina's SNP technology and the preliminary human HapMap data.

The genetics of human severe pediatric gastroensophageal reflux disease

Files and links (1)

Abstract

Metrics

Details

The genetics of human severe pediatric gastroensophageal reflux disease

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media