A number sign (#) is used with this entry because of evidence that gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2) is caused by homozygous mutation in the PI4KA gene (600286) on chromosome 22q11.

Gastrointestinal defects and immunodeficiency syndrome-2 (GIDID2) is a severe autosomal recessive developmental disorder characterized by multiple intestinal atresia apparent soon after birth. Affected infants have a distended abdomen and do not pass meconium. There is some evidence of inflammatory bowel disease. Death occurs in the first weeks of life. Some patients may also have immunodeficiency (summary by Salter et al., 2021).

For a discussion of genetic heterogeneity of GIDID, see GIDID1 (243150).

Salter et al. (2021) reported a large multigenerational consanguineous Amish kindred (family 1) in which multiple infants were affected with severe multiple intestinal atresia (MIA) presenting soon after birth and resulting in death in all infants within the first months of life. There was evidence of third trimester polyhydramnios in affected pregnancies. The patients had symptoms of bowel obstruction with abdominal distension, bilious vomiting, and inability to pass meconium. Explorative abdominal surgery performed in some patients showed multiple sections of abnormal, inflamed, and atretic bowel from pylorus to anus. Bowel histology showed multiple lumen anlagen, intestinal cysts, loss of epithelial layer, mild inflammatory infiltrate, and fibrous lumen accumulation. No neurologic abnormalities were detected. One patient had intermittent lymphopenia with 1 episode of severe lymphopenia, whereas another showed a severe T-cell lymphopenia, moderate B- and NK-cell lymphopenia, and agammaglobulinemia. The families opted for palliative care.

The transmission pattern of GIDID2 in the families reported by Salter et al. (2021) was consistent with autosomal recessive inheritance.

In 5 infants from a large multigenerational consanguineous Amish kindred (family 1) with GIDID2, Salter et al. (2021) identified a homozygous missense mutation in the PI4KA gene (Y1623D; 600286.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that the variant displayed normal catalytic activity, but had impaired interaction with its partner TTC7A (609332), rendering the overall complex unstable. The authors noted that TTC7A is expressed in the intestine at higher levels than in the brain, which may explain the predominantly gastrointestinal manifestations in these patients. Mutation in the TTC7A gene can cause a disorder with overlapping gastrointestinal manifestations (GIDID1; 243150).