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

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Gastrointestinal defects and immunodeficiency syndrome 1 (GIDID1) is a rare autosomal recessive disorder.
• It is caused by biallelic variants in the TTC7A gene.
• GIDID1 presents a spectrum from very early-onset inflammatory bowel disease (VEOIBD) to multiple intestinal atresia (MIA), with or without immunodeficiency.

Purpose of the Study:

• To report a novel TTC7A loss-of-function (LOF) variant in a patient with severe GIDID1.
• To perform a systematic literature review and genotype-phenotype correlation analysis of 87 patients.
• To refine genotype-phenotype correlations for TTC7A-associated GIDID1.

Main Methods:

• Case report of a patient with a novel homozygous TTC7A LOF variant.
• Systematic literature review.
• Genotype-phenotype correlation analysis.

Main Results:

• The patient presented with MIA, combined immunodeficiency, and died at 11 months.
• A strong association exists between biallelic TTC7A LOF variants and MIA with severe combined immunodeficiency.
• Biallelic TTC7A missense variants are more frequently linked to milder phenotypes like VEOIBD.
• TTC7A LOF variants correlate with reduced life expectancy (median survival 9 months vs. 33.5 months for missense variants).

Conclusions:

• Findings refine genotype-phenotype correlations for TTC7A-associated GIDID1.
• Provides insights for genetic counseling, disease management, and treatment strategies.
• Highlights the distinct clinical outcomes associated with TTC7A LOF versus missense variants.