Gastrointestinal Defects and Immunodeficiency Syndrome is a rare genetic disorder characterized by abnormalities in both the gastrointestinal system and the immune system, which presents clinically as immunodeficiency, very early onset inflammatory bowel disease (VEOIBD) and/or multiple intestinal atresia (MIA) (1–3). Individuals with this condition are prone to premature birth and face an extremely severe prognosis with high early mortality. Notably, over half die before their first year of life (3–6).

GIDID is inherited in an autosomal recessive pattern, with molecular genetic studies establishing its association with biallelic mutations in the TTC7A gene located at chromosome 2p21 (4, 7). The TTC7A gene product, a critical regulatory protein, is essential for the proper development and homeostasis of both intestinal epithelial cells and lymphocytes. Molecular analyses have demonstrated that loss-of-function mutations within the tetratricopeptide repeat (TPR) domains disrupt critical protein-protein interactions and transcriptional regulation processes (1, 8, 9). At the cellular level, TTC7A deficiency manifests through distinct pathogenic mechanisms in different cell types. In enterocytes, the impaired regulatory control over the RhoA signaling pathway results in profound disruptions of apicobasal polarity (2). Concurrently, in the lymphoid compartment, thymic T cells exhibit defective proliferation, impaired adhesion capacity, and aberrant migratory patterns (10). These cellular disturbances collectively contribute to the characteristic pathological features of GIDID, including progressive apoptotic enteropathy and profound lymphocyte depletion, ultimately leading to the reversal of cellular polarity.

The prenatal manifestations of GIDID remain poorly characterized in current literature. In a seminal study conducted by Amelie Busolin’s research team, comprehensive antenatal findings were documented in 30 affected patients. The most prevalent ultrasonographic features included intestinal dilatation/atresia (n=19), hydramnios/polyhydramnios (n=14), and intraluminal calcifications (n=10) (6). Given the profound implications for clinical management, the establishment of a definitive genetic diagnosis through prenatal testing is essential for informed therapeutic decisions. Current guidelines recommend the implementation of whole-exome sequencing (WES) as a first-tier diagnostic approach when severe fetal structural abnormalities are detected, particularly those involving the gastrointestinal tract.

In this study, we present a prenatal case of gastrointestinal defects and dysplasia in a fetus from a non-consanguineous couple. Comprehensive prenatal evaluation through whole-exome sequencing revealed compound heterozygous mutations (c.2378del and c.2357G>T) in the TTC7A gene, both classified as pathogenic variants according to ACMG guidelines. This molecular confirmation enabled the definitive prenatal diagnosis of GIDID. While the prenatal presentation of GIDID remains poorly documented in the literature, our findings contribute to the expanding knowledge of its fetal manifestations. This investigation not only broadens the mutational spectrum of the TTC7A gene but also demonstrates the diagnostic efficacy of integrating advanced ultrasonography with fetal whole-exome sequencing for prenatal identification of GIDID.

GIDID is a rare and severe clinical disorder first documented in 1974 (11). The condition was initially characterized by the presence of multiple intestinal atresias in patients from consanguineous families (12). Clinically, GIDID manifests as multiple intestinal atresias accompanied by varying degrees of severe immunodeficiency or sepsis. Additionally, some patients develop inflammatory changes in the small intestine or colon, or experience recurrent intestinal strictures (13–15). In a comprehensive classification by Amelie Busolin and colleagues, three distinct phenotypic presentations were identified based on the triad of primary clinical features (multiple intestinal atresia, immune deficiency, and enteropathy): (1) immune deficiency with multiple intestinal atresia without enteropathy (ID/MI), (2) immune deficiency with enteropathy without atresia (ID/E), and (3) immune deficiency with both multiple intestinal atresia and enteropathy (ID/MIA/E) (4). The prognosis of GIDID remains generally poor, with most cases presenting severe, early-onset symptoms that contribute to high mortality rates within the first year of life. Amelie Busolin et al. reported a mortality rate of 65.8% in GIDID, with a mean age of death at 11.8 months. Clinical observations indicate that patients with the ID/MIA phenotype tend to have earlier mortality compared to those with the ID/E phenotype (4). Zhaowei Huang et al. conducted a review of GIDID cases caused by TTC7A mutations and found that among the 89 reported patients, the majority had a poor prognosis, with 52.8% deceased and 43.8% surviving. The median age of the deceased and surviving patients was 1.83 years and 0.92 years, respectively, with most deaths occurring before the age of two (16).

Recent advances in genetic research have significantly enhanced our understanding of the molecular basis of GIDID, with a growing body of literature identifying TTC7A mutations as the most prevalent pathogenic variant associated with this condition (6). However, current evidence suggests that the contribution of genetic factors to GIDID pathogenesis remains substantially underestimated. The precise identification of genetic causes plays a pivotal role in clinical management, as it not only facilitates accurate prognosis but also enables reliable estimation of recurrence risks and informs evidence-based therapeutic strategies.

The TTC7A gene, located on chromosome 2p21, comprises 20 exons and encodes a protein of 858 amino acids (17). This gene exhibits widespread expression across multiple tissues and organs, including the brain, bone marrow, testes, pancreas, ovaries, liver, and blood. The encoded TTC7A protein is structurally characterized by the presence of tetratricopeptide repeat (TPR) domains, which are defined by a degenerate consensus sequence of 34 amino acids typically arranged in tandem arrays (18). TPR domain-containing proteins, such as TTC7A, are known to participate in a wide range of critical biological processes, including transcriptional regulation, mitochondrial and peroxisomal protein transport, protein kinase inhibition, cell cycle control, NADPH oxidase activity modulation, and viral replication (19).

Recent studies indicate that TTC7A plays a crucial role in the development and maintenance of intestinal epithelial cells. TTC7A contains nine tetratricopeptide repeat (TPR) domains, which are well-conserved structural motifs frequently observed in proteins involved in cellular trafficking and scaffolding processes (20). Functionally, TTC7A serves as a scaffold protein that facilitates the transport of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) to the plasma membrane. At this site, PI4KIIIα catalyzes the phosphorylation of phosphatidylinositol (PI) to generate phosphatidylinositol 4-phosphate (PI4P) (1). The maintenance of optimal PI4P levels is critical for several cellular processes, including plasma membrane identity establishment, apicobasal polarity formation, cell survival regulation, and the biosynthesis of poly-phosphorylated phosphatidylinositol phosphate lipids such as PI(4,5)P2 and PI(3,4,5)P3. Notably, the synthesis of plasma membrane PI4P is entirely dependent on the proper function and localization of PI4KIIIα (21–23). AKT, a key survival kinase, exerts its protective effects through phosphorylation-mediated activation, which subsequently inhibits apoptosis, promotes cellular proliferation, enhances protein synthesis, and regulates metabolic processes (23). In the context of TTC7A deficiency, studies have demonstrated a marked reduction in phosphorylated AKT (p-AKT) levels within the intestinal epithelium, while total AKT levels remain relatively stable. This observation suggests that impaired AKT activation, as reflected by diminished p-AKT levels, may represent a critical mechanism underlying the pathophysiology of TTC7A deficiency (7).

Research conducted by several scholars has demonstrated that mutations in the TTC7A gene, leading to TTC7A deficiency, disrupt the RhoA signaling pathway (2). Although this disruption does not prevent intestinal development, it partially compromises epithelial cell polarity and intestinal homeostasis. Specifically, TTC7A deficiency results in the abnormal phosphorylation of key ROCK effectors, including ezrin-radixin-moesin (ERM) proteins and myosin light chain (MLC), which are critical regulators of cell adhesion, polarization, and migration (24–26). Furthermore, in T lymphocytes, TTC7A deficiency has been shown to impair their proliferation, adhesion, and migration within the thymus, highlighting the broader systemic impact of TTC7A dysfunction beyond the intestinal epithelium (27).

A research team developed mouse models, including the flaky skin mutant (fsn), hereditary erythroblastic anemia (hea), and INT mutants (int), which revealed spontaneous mutations in the TTC7A gene (28). Pathological analysis of these models demonstrated significant gastric abnormalities, including extensive papillomatosis of the stratified squamous epithelium in the forestomach, elevated apoptosis of cecal enterocytes, and a moderate mixed inflammatory cell infiltrate within the lamina propria. Furthermore, some mice exhibited a hyperproliferative immune disorder characterized by splenomegaly, lymphadenopathy (marked by the accumulation of T and B lymphocytes), and systemic autoimmune features that persisted over time. The structural similarity between mouse and human TTC7A orthologs is notable, with both species sharing 20 exons that encode an 858-amino acid protein containing 7 TPR motifs, resulting in a 96 kDa protein. These findings provide compelling evidence that defects in the TTC7A gene are directly associated with gastrointestinal abnormalities and immune dysregulation (29–32).

In conclusion, we present a rare case of prenatal diagnostic imaging in GIDID fetuses caused by TTC7A gene mutations, a clinical presentation that has been scarcely documented in the literature. In this case, the observed fetal phenotype is highly consistent with the identified genotype, providing strong clinical evidence supporting the pathogenicity of both variants. Protein structure predictions revealed that the c.2357G>T missense variant causes a significant structural disruption, while c.2378del frameshift mutation alters an amino acid residue. Although the c.2378del frameshift mutation did not result in a marked alteration of the predicted overall protein structure, we infer that the resulting glycine-to-alanine substitution—despite involving two amino acids with similar physicochemical properties—may occur within a functionally critical domain, thereby disrupting protein function. This case not only expands the known clinical phenotype of the disease but also highlights the critical importance of early detection and accurate diagnosis. For fetuses exhibiting gastrointestinal abnormalities and/or immune dysfunction, GIDID should be included in the differential diagnosis, and prompt genetic testing for TTC7A mutations is strongly recommended to facilitate timely clinical management.