CoGenesis® Gastroenterological

CoGenesis® Gastroenterological is a comprehensive next-generation sequencing (NGS) panel covering 312 genes across the spectrum of rare hereditary gastrointestinal and hepatic disorders. The panel is potentially useful for patients who have undergone extensive clinical investigation without a definitive diagnosis.

Identifying a genetic cause of a hereditary gastrointestinal disorder may change clinical management, guide treatment selection, enable cascade family testing, informs reproductive planning.

Liver and biliary disorders: The panel covers hereditary cholestatic diseases including Progressive Familial Intrahepatic Cholestasis (PFIC) caused by mutations in ABCB11, ATP8B1, ABCB4, TJP2, and NR1H4; bile acid synthesis defects (CYP7A1, CYP7B1, HSD3B7, AKR1D1, CYP27A1); Alagille syndrome (JAG1, NOTCH2); Wilson disease (ATP7B); hereditary haemochromatosis (HFE, HFE2, TFR2); alpha-1 antitrypsin deficiency (SERPINA1); Dubin-Johnson syndrome (ABCC2); hereditary tyrosinaemia type 1 (FAH); lysosomal acid lipase deficiency/Wolman disease (LIPA); and Niemann-Pick disease (SMPD1, NPC1, NPC2).

Inflammatory bowel disease and immune dysregulation: Monogenic causes of early-onset IBD are covered through IL10, IL10RA, IL10RB (IL-10 signalling defects), NOD2, ATG16L1, IL23R (Crohn’s susceptibility), FOXP3 (IPEX syndrome), XIAP, LRBA, PIK3CD, PIK3R1, STAT1, and STAT3. Chronic Granulomatous Disease (CYBA, CYBB, NCF1, NCF2, NCF4) and other primary immunodeficiencies manifesting as GI disease are also included.

Intestinal motility and structural disorders: Hirschsprung disease is comprehensively covered through its known genetic causes including RET, EDNRB, EDN3, GDNF, GFRA1, SOX10, PHOX2B, and additional neural crest genes. Intestinal pseudo-obstruction (ACTG2, FLNA, MYH11), microvillus inclusion disease (MYO5B), multiple intestinal atresia (TTC7A), and other motility disorders are included.

Malabsorption and congenital enteropathies: Galactosaemia (GALT, GALE, GALK1, GALM), hereditary fructose intolerance (ALDOB), glycogen storage disorders (GBE1, SLC37A4, G6PC3), trichohepatoenteric syndrome (TTC37, SKIV2L), and congenital diarrhoeas caused by ion transporter defects (SLC9A3, SLC10A2) are covered.

Peroxisomal disorders with GI involvement: The complete set of PEX genes (PEX1–PEX26) for Zellweger spectrum disorders, and D-bifunctional protein deficiency (HSD17B4) are included.

Polyposis and hereditary colorectal syndromes: PTEN (Cowden/PTEN hamartoma tumour syndrome), EPCAM (Lynch syndrome), and PTCH1 (Gorlin syndrome with GI polyposis) are covered.

1. Infants or children presenting with unexplained neonatal or early-onset cholestasis, conjugated hyperbilirubinaemia, or progressive liver disease in whom standard workup has not identified a cause, including suspected PFIC, bile acid synthesis defects, or Alagille syndrome.
2. Patients with early-onset or very-early-onset inflammatory bowel disease (before age 6), refractory IBD, or IBD associated with features suggesting a primary immunodeficiency (IPEX, IL-10 signalling defects, Chronic Granulomatous Disease, XIAP deficiency).
3. Neonates or children with suspected Hirschsprung disease or chronic intestinal pseudo-obstruction requiring molecular classification for surgical planning and assessment of syndromic associations (neural crest disorders, MMIHS).
4. Patients with unexplained malabsorption, congenital diarrhoea, or suspected inborn errors of carbohydrate or fatty acid metabolism (galactosaemia, hereditary fructose intolerance, glycogen storage disorders, trichohepatoenteric syndrome, or peroxisomal disorders).
5. Individuals with suspected hereditary polyposis or familial colorectal cancer syndromes (Cowden/PTEN hamartoma tumour syndrome, Lynch syndrome, Gorlin syndrome) or hereditary metabolic liver conditions (Wilson disease, hereditary haemochromatosis, alpha-1 antitrypsin deficiency) requiring molecular confirmation.

6 sub-panels included:

4mL Peripheral blood (EDTA), 2mL saliva, or buccal swab

Preferred sample type:

• 4mL Blood (EDTA tube),
• Codex-provided buccal swabs (4 swabs)
• Codex-provided saliva collection kit (2mL)

Saliva or buccal swab sample collection: Follow the enclosed instructions; do not eat, drink, or smoke for 30 minutes before collection.

• Results may identify pathogenic, likely pathogenic, or variants of uncertain significance (VUS).
• Positive findings can inform risk‑reducing strategies and treatment options.
• Genetic counseling is recommended to help families understand implications.

Hereditary gastrointestinal disorders encompass a clinically diverse group of rare conditions affecting the liver, biliary system, intestines, and the enteric nervous system. They frequently present in infancy or childhood with nonspecific features such as neonatal jaundice, chronic diarrhoea, failure to thrive, or recurrent abdominal pain. Without a genetic diagnosis, patients often undergo prolonged and invasive diagnostic workups before a definitive cause is identified.

Hereditary liver and biliary disorders represent one of the largest genetic subcategories. Progressive Familial Intrahepatic Cholestasis (PFIC), caused by defects in hepatocanalicular transporters (ABCB11, ATP8B1, ABCB4) and tight junction proteins (TJP2), has a combined prevalence estimated at 1 in 50,000–100,000; molecular diagnosis guides eligibility for ileal bile acid transporter (IBAT) inhibitors. Wilson disease (ATP7B) affects approximately 1 in 30,000 and is treatable with chelation therapy. Alpha-1 antitrypsin deficiency (SERPINA1) — the most common inherited liver disease — affects 1 in 2,500–3,500 Europeans. Alagille syndrome (JAG1, NOTCH2) affects 1 in 30,000–50,000 live births with characteristic bile duct paucity, cardiac, and vertebral anomalies.

Monogenic inflammatory bowel disease (IBD) accounts for a disproportionate fraction of very-early-onset IBD (VEO-IBD), defined as onset before age 6. Over 80 genes have been identified as Mendelian causes of VEO-IBD, including IL10/IL10RA/IL10RB (IL-10 signalling pathway), FOXP3 (IPEX syndrome), XIAP, LRBA, PIK3CD/PIK3R1 (APDS), and NOD2. Primary immunodeficiencies presenting as IBD — such as Chronic Granulomatous Disease (CGD; CYBA, CYBB, NCF1/2/4) — may be treatable with haematopoietic stem cell transplantation (HSCT), making early genetic diagnosis life-changing. Diagnostic yield for monogenic causes in VEO-IBD ranges from 15–50% depending on age of onset and clinical features.

Hirschsprung disease (HSCR), caused by failure of neural crest cell migration to the distal gut, affects approximately 1 in 5,000 live births and is the most common cause of neonatal intestinal obstruction. RET is the major susceptibility gene, accounting for 50% of familial and 15–20% of sporadic cases; additional genes include EDNRB, EDN3, GDNF, SOX10, and PHOX2B. Molecular diagnosis identifies syndromic associations (Waardenburg-Shah, Mowat-Wilson, congenital central hypoventilation syndrome) critical for multidisciplinary management. Chronic intestinal pseudo-obstruction (CIPO), caused by smooth muscle myopathies (ACTG2, FLNA, MYH11), is a distinct disorder with marked morbidity and different surgical indications.

Since the same phenotype (e.g., neonatal cholestasis, early-onset IBD, intestinal obstruction) can arise from dozens of distinct genetic aetiologies, CoGenesis® Gastroenterological may help delineate the genetic complexity and clinical overlap inherent in hereditary GI diseases.