Diarrhea 6

A number sign (#) is used with this entry because of evidence that this form of congenital diarrhea, designated DIAR6, is caused by heterozygous mutation in the GUCY2C gene (601330) on chromosome 12p12.

Description

Diarrhea-6 is a relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis (Fiskerstrand et al., 2012).

For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).

Clinical Features

Fiskerstrand et al. (2012) studied 32 affected and 14 unaffected individuals from 3 branches of a large pedigree segregating autosomal dominant early-onset chronic diarrhea. The diarrhea started in infancy and was fairly constant over the years, but improved by middle age in some. Patients had an average of 3.6 stools per day, which typically were watery or of loose consistency and were accompanied by gaseous distention of the abdomen (meteorism) and in some cases abdominal pain. Eight patients were hospitalized as newborns for dehydration, metabolic acidosis, and electrolyte disturbances. Four family members had been diagnosed with irritable bowel syndrome although they did not meet strict criteria for diagnosis; however, 5 other cases did meet the criteria. Most family members reported food sensitivities, and several limited their intake of fruits, vegetables, and sweets. Ten patients underwent laparotomy for suspected bowel obstruction, and in 8 cases, obstruction due to volvulus, adhesions, or ileal inflammation was confirmed. Of 5 patients who underwent bowel resection, 4 had verified or suspected Crohn disease (see 266600), as did 3 other affected family members, and another patient was diagnosed with possible eosinophilic enteritis. Fiskerstrand et al. (2012) noted that there were several other conditions present in affected family members that might be associated with the inherited disorder, including vitamin B12 deficiency in 6 patients, esophagitis with or without esophageal hernia in 5, and urolithiasis in 4.

Mapping

Fiskerstrand et al. (2012) performed linkage analysis using DNA samples from 11 affected and 14 unaffected members of a large pedigree segregating autosomal dominant early-onset chronic diarrhea and identified only 1 significant shared region among affected members, a 2.9-Mb interval on chromosome 12p (chr12:14,466,726-17,410,570, NCBI36), with a maximum lod score of 5.1. There was complete segregation with disease in the family.

Molecular Genetics

In a large pedigree with early-onset chronic diarrhea mapping to chromosome 12p, Fiskerstrand et al. (2012) sequenced the candidate gene GUCY2C (601330) and identified a heterozygous missense mutation (S840I; 601330.0001) that segregated with the disease and was not found in 190 healthy local blood donors or in the NCBI human dbSNP database (build 132). Whole-exome sequencing in 1 patient from each of 3 branches of the pedigree did not identify any other rare coding variant, and the S840I mutation was confirmed to be present in all affected family members by Sanger sequencing. Functional analysis suggested that the mutation represented a gain-of-function change.