Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14

Abstract

Context: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms.

Objective: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members.

Design: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses.

Setting: General US community, with research performed in a university tertiary care hospital.

Subjects: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group.

Main outcome measures: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage.

Results: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected).

Conclusion: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334

Figure 1.

Pedigree of Family L (Families 2, 3, and 4) Showing Multiple Members Affected With Severe Pediatric Gastroesophageal Reflux

Figure 2.

Pedigrees and Haplotype Data for All Study Families Showing Multiple Members Affected With Severe Pediatric Gastroesophageal Reflux See key to Figure 1 for explanation of symbols. The bars in Panels A through D represent haplotypes including markers D13S171, D13S218, D13S1288, D13S1253, D13S263, D13S1297, D13S1272, D13S153, and D13S155 (from centromere to telomere, respectively). Numbers beside the bars indicate allele sizes according to a simple ordered numbering of allele values for each marker (thus, a size of 7 indicates that at least 7 alleles exist for a marker). The symbol”?” indicates allele was not determined or inferable. Parenthetical allele sizes indicate an inferred haplotype. A bar of 1 pattern indicates no recombinations from the previous generations assuming maximum parsimony; wherever parental homozygosity makes it impossible to determine phase a question mark is placed beside the binned allele values. Within each family, individuals with the same bar type share a common haplotype. SN indicates study number. Study numbers 015 and 039 were identical twins (see Figure 1); because SN 039 was deceased, we used data from SN 015 in haplotype construction. Allele comparison between SN 015 and nephew SN 029 showed 399/400 markers as identical, confirming identical twin status.

Figure 3.

Multipoint Lod Scores Graphical representation of the multipoint data generated by Linkmap of the Fastlink software program showing the logarithm-of-odds (lod) score on the y axis and the microsatellite marker positions in cM on the x axis. Panel A displays data obtained when all individuals who were presumptively (but not definitively) affected were modeled as unaffected. Panel B displays data obtained when presumptively affected individuals were modeled as unknown. These computer-generated curves do not show the x axis drawn exactly to scale.

Figure 4.

Location of the Severe Pediatric GER Gene on Chromosome 13 Line diagram of chromosome 13 showing the position of the severe pediatric gastroesophageal reflux (GER) gene and the distance of the microsatellite markers in cM from the p telomere that were used in mapping and refining the locus, p Indicates the short arm of the chromosome; q, the long arm of the chromosome.