Autosomal dominant infantile gastroesophageal reflux disease: exclusion of a 13q14 locus in five well characterized families.

Objectives: A genetic locus for pediatric reflux was proposed on chromosome 13q14, but is unconfirmed in independent kindreds. We sought to test this locus in families with multiple affected infants from our database of well characterized infants with reflux.

Methods: We screened the database for families with multiple affected infants. Affected proband phenotype required histological esophagitis; affected sibling/cousin phenotype required a threshold score on a diagnostic questionnaire. Screened families were reduced to five based on pedigree, consent, and phenotypic clarity. Linkage of the phenotype with the four previously reported markers (D13S218, D13S1288, D13S1253, and D13S263) was tested, using an autosomal dominant, 70% penetrance model. Linkage required logarithm-of-odds score > or = 3.

Results: Of 54 individuals in the five probands' generation, 21 (39%) were affected based on questionnaire, of whom nearly one half also had histological confirmation of esophagitis. Linkage to the defined region was excluded for the five families by two-point LOD scores (-1.47 at D13S218, -1.32 at D13S1288, -3.43 at D13S1253, and -3.92 at D13S263) and by multipoint (multipoint LOD scores less than -2 between D13S218 and D13S263) linkage analysis. No family demonstrated even suggestive positive linkage (i.e., LOD score >1).

Conclusions: In five rigorously phenotyped families with autosomal dominant pattern infantile reflux, we excluded genetic linkage to the region of 13ql4 previously identified responsible for an autosomal dominant form of pediatric reflux. These results suggest genetic heterogeneity, possibly related to phenotypic heterogeneity, in familial pediatric gastroesophageal reflux disease.