Genotype-Phenotype Correlation in TTC7A -Associated Gastrointestinal Defects and Immunodeficiency Syndrome 1

Gastrointestinal defects and immunodeficiency syndrome 1 (GIDID1) is a rare autosomal recessive disorder caused by biallelic variants in TTC7A. GIDID1 is characterized by a broad clinical spectrum ranging from very early-onset inflammatory bowel disease (VEOIBD) to multiple intestinal atresia (MIA) with or without immunological manifestations. We report a patient born to consanguineous parents carrying a novel homozygous TTC7A loss-of-function (LOF) variant, NM_001288951.2:c.1322_1323del; p.(Val441Glufs*57). The patient presented with MIA, requiring permanent parenteral nutrition, combined immunodeficiency, anemia, and congenital heart defects, and died at 11 months of age. To improve prognostic insights, we performed a systematic literature review and genotype-phenotype correlation analysis on 87 genetically revised patients, including our case. Our findings confirm a strong association between biallelic TTC7A LOF variants and MIA with (severe) combined immunodeficiency, often necessitating parenteral nutrition. In contrast, biallelic TTC7A missense variants were more frequently linked to milder GIDID1-associated phenotypes, such as VEOIBD. The presence of at least one TTC7A LOF variant correlated with a stronger reduced life expectancy, with a median survival of 9 months compared to 33.5 months in patients with biallelic TTC7A missense variants. Our findings refine genotype-phenotype correlations of TTC7A-associated GIDID1, providing valuable insights for genetic counseling, disease management, and treatment strategies.