Gastrointestinal
for metabolic and chronic GI disorders with exome sequencing
System Profile
Yield Comparison
Clinical Dimensions
- FTT despite adequate intake
- Chronic diarrhea
- Severe constipation
- Vomiting
- Hepatosplenomegaly
- Feeding intolerance
- Hirschsprung disease
- Chronic pancreatitis in youth
- Congenital microvillus inclusion disease
- Biliary atresia with syndromic features
- Intestinal pseudo-obstruction
- Hepatosplenomegaly
- Abdominal distension
- Poor suck
- FTT signs
- Jaundice
- Surgical scars for congenital GI anomalies
- Ascites
- Palpable stool burden
- Poor weight gain
- Chronic constipation or diarrhea
- Recurrent vomiting
- Abdominal pain
- Greasy stools
- Feeding refusal
- Persistent GERD
- Elevated AST/ALT
- Cholestatic pattern (direct hyperbilirubinemia)
- High GGT
- Low pancreatic elastase
- Elevated ammonia
- Abnormal serum amino acids
- Abnormal stool fat or A1AT
- Abdominal US with hepatosplenomegaly
- Biliary atresia signs
- Congenital malrotation
- Pancreatic atrophy (CF)
- Intestinal dilation (pseudo-obstruction)
- Absent gallbladder
- Endoscopy with villous atrophy or microvillus inclusion
- Motility studies showing pseudo-obstruction
- Fecal fat or A1AT abnormal
- Sweat test confirming CF GI involvement
- Pancreatic enzymes
- Chronic stool softeners
- Proton pump inhibitors for severe GERD
- TPN
- Specialized formulas
- Bile acid medications
- Food protein-induced enteropathies or non-IgE mediated reactions in infancy that align with genetic GI disorders
- Persistent intolerance despite avoidance
- G-tube or J-tube placement
- Malrotation or atresia repair
- Colectomy for Hirschsprung
- Surgery for intestinal pseudo-obstruction
- Feeding therapy for oral aversion, dysphagia, behavioral feeding issues
- Specialized nutrition programs for FTT
- G-tube/J-tube
- Feeding pumps
- TPN ports
- Ostomy appliances
- Pediatric GI and hepatology
- Feeding team
- Nutrition
- Motility specialists
- GI/hepatology recommending metabolic/genetic evaluation
- Hirschsprung disease
- Recurrent pancreatitis
- Chronic GI issues
- Liver disease in multiple relatives
- FTT patterns in siblings
- Adequate access to food but persistent FTT
- Good hygiene but chronic GI infections
- GI symptoms since early infancy unrelated to diet quality
- Feeding intolerance
- Bilious emesis
- Congenital malformations (TEF, duodenal atresia)
- Abdominal distension
- Hepatosplenomegaly
- Severe reflux
- Early FTT
Red Flag Combinations
Clinical patterns that should prompt consideration of genetic testing
FTT + hypotonia
Hepatosplenomegaly + anemia
Hirschsprung + other anomalies
Recurrent pancreatitis + hearing loss
Screening Decision Pathway
When to consider genetic testing for gastrointestinal presentations
graph TD
START["Patient Presents with\nGastrointestinal Concerns"] --> SCREEN{"Screen for\nRed Flags"}
SCREEN --> RF1["Positive FTT screens"]
SCREEN --> RF2["Abnormal nutrition or malnutrition screening tools"]
SCREEN --> RF3["Positive CF GI screens"]
SCREEN --> RF4["Celiac serology with atypical features"]
RF1 --> EVAL{"Multiple\nFlags Present?"}
RF2 --> EVAL{"Multiple\nFlags Present?"}
RF3 --> EVAL{"Multiple\nFlags Present?"}
RF4 --> EVAL{"Multiple\nFlags Present?"}
EVAL -->|Yes| TEST["Order Genetic Testing\n(ES/GS)"]
EVAL -->|No| MONITOR["Continue Monitoring\nRe-evaluate if New Findings"]
TEST --> DX["Molecular Diagnosis\n25-64% yield"]
style TEST fill:#dcfce7,stroke:#16a34a,color:#14532d
style DX fill:#bbf7d0,stroke:#16a34a,color:#14532d
style MONITOR fill:#fef3c7,stroke:#d97706,color:#92400e
Screening Red Flags
Findings on routine screening that may indicate genetic etiology
- Positive FTT screens
- Abnormal nutrition or malnutrition screening tools
- Positive CF GI screens
- Celiac serology with atypical features
Exome / Genome Sequencing Indications
Clinical scenarios supporting ES/GS as a diagnostic approach
- Severe FTT
- Chronic GI dysfunction
- Hirschsprung or complex malformations
- Pancreatitis in youth
- Hepatosplenomegaly
- Unclear GI/metabolic syndrome after first-tier workup
Key Evidence
Published studies supporting genetic testing for gastrointestinal conditions
| Study | Year | Type | Sample | Yield | Key Finding |
|---|---|---|---|---|---|
| Next-Generation Sequencing to Diagnose Suspected Genetic Dis... | 2018 | Review | None | 25-52% | 25-52% diagnostic yield for suspected genetic disorders with exome sequencing; t... |
| Very Early Onset Inflammatory Bowel Disease: An Integrated A... | 2018 | Review | None | None | VEO-IBD has high rate of monogenic etiology requiring integrated genomic and imm... |
| CARMIL2 Deficiency as a Cause of Very Early Onset Inflammato... | 2019 | Cohort | None | None | WES identified CARMIL2 deficiency as monogenic cause of VEO-IBD with combined im... |
| NLRP3 Gain-of-Function Variant in Very Early Onset Inflammat... | 2020 | Cohort | None | None | WES discovered novel NLRP3 gain-of-function variant as cause of VEO-IBD with aut... |
| Clinical Genomics for the Diagnosis of Monogenic Forms of In... | 2021 | Guideline | None | 15-20% | ESPGHAN recommends NGS with targeted panel for very early-onset IBD (<6 years); ... |
Updated: 2026-02-24
Curated by: human
Status: human reviewed