Identifying Genetic Cause of Neurodevelopmental Disorder May Help Understand Severity of Gastrointestinal Dysfunction

A study of nearly 3000 pediatric patients with neurodevelopmental disorders (NDDs) revealed that those with an identified genetic cause had significantly higher rates of gastrointestinal (GI) diagnoses relative to those with idiopathic NDDs. Overall, these findings further stress the importance of identifying genetic etiology and considering the gastrointestinal needs of patients with NDDs.¹

Led by Sherilynn Knight, MS, of the Geisinger Health System, the study comprised 2924 pediatric patients with NDDs, 824 of whom had an identified genetic etiology. Overall, GI diagnoses were found in 62.0% of those with an identified genetic cause vs 54.6% of those with non-causative NDD (P <.001). Similarly, the study authors found higher rates of other congenital malformations (6.6% vs 3.2%; P <.001) as well as other intestinal diseases (31.8% vs 23.3%; P <.001) among those with causative NDD.

Presented at the 44th National Society of Genetic Counselors (NSGC) Annual Conference, held November 6–10 in Seattle, Washington, the study compared GI diagnosis frequency and distribution in pediatric patients with genetic versus idiopathic neurodevelopmental disorders (NDDs). Knight and colleagues also examined links between specific genetic etiologies, GI manifestations, and genes expressed in the developing enteric nervous system.

Additional results from the study showed that those with an identified genetic cause of NDD had higher signs and symptoms involving the digestive system (39.8% vs 32.5%; P <.001), as well as more diseases of the esophagus, stomach, and duodenum (24.4% vs 15.5%; P <.001). Furthermore, this group also showed higher rates of noninfective enteritis and colitis (7.5% vs 4.2%; P <.001), symptoms and signs concerning food and fluid intake (37.5% vs 28.8%; P <.001), and other diseases of the digestive system (7.5% vs 4.8%; P = .004).

Knight and her colleagues also grouped the genes by how they function within a patient with NDD. The groups included (1) chromatin remodeling & gene expression regulation, (2) mitochondrial function & metabolism, (3), ion transport & ATP utilization, (4), RNA & gene silencing, and (5) cell signaling & structural roles. Across all these groups, the patient count was higher than the unique gene count (group 1: 149 vs 80; group 2: 11 vs 8; group 3: 47 vs 28; group 4: 6 vs 5; group 5: 125 vs 77).

Across all groupings, 65-70% of patients had at least 1 GI diagnosis. When looking at the specific genetic expression, most identified genes impacted the enteric nervous system (ENS). Overall, there were 317 with ENS expression, 5 without, and 16 with unknown expression.

The study authors noted that future directions should include incorporating more diverse populations across multiple health systems to improve the generalizability of findings. The investigators also aim to perform more specific cell analyses to better capture ENS expression, with current gene classifications providing a foundation for this work. Additionally, future studies plan to include CNV and karyotype NDD results, which were excluded from the current analysis due to time constraints. Expanding to larger cohorts will also allow for more detailed evaluation of gene-specific gastrointestinal manifestations and their relationships with neurodevelopmental disorders.

Click here for more NSGC 2025 coverage.

REFERENCE
1. Knight SG, Myers SM, Mills R, et al Characterizing Genetic Causes of Neurodevelopmental Disorders and Associated Gastrointestinal Dysfunction in Children. Presented at: 2025 NSGC Annual Conference; November 6-10; Seattle, Washington. Abstract QUAN431