1. NGS Panel – Genetic Testing for Pancreatitis


March 09, 2018

Disease summary:

Pancreatitis is a common inflammatory disorder of the pancreas 1. There are a variety of disorders of the pancreas including acute pancreatitis 2, chronic pancreatitis 3, hereditary pancreatitis, and pancreatic cancer. The majority of hereditary pancreatitis are caused by heterozygous pathogenic variants in PRSS1, or biallelic variants in SPINK1 and CFTR. Also, familial pancreatitis is also caused by pathogenic variants in genes that affect trypsin regulation, e.g. CTRC.

Autosomal dominant, autosomal recessive

Incidence for acute pancreatitis: 13-45/100,000 4, 5

Incidence for chronic pancreatitis: 50/100,000 6, 7

Major clinical symptoms for acute pancreatitis include the following 1, 2:

  • Sudden onset of typical epigastric abdominal pain
  • Elevation of serum amylase or lipase more than three times the upper limits of normal
  • Characteristic findings of acute pancreatitis (pancreatic edema, fat stranding, peripancreatic fluid accumulation)                         

Major clinical features for chronic pancreatitis are the following 3:

  • Abdominal imaging (inflammatory masses; pancreatic parenchyma and ductal calcifications; pseudocysts)
  • Functional studies (pancreatic exocrine insufficiency, maldigestion of food, pancreatic endocrine insufficiency)
  • Histologic changes (atrophy, fibrosis, and/or sclerosis)

Diagnostic criteria for acute pancreatitis 2, 8:

  • Characteristic upper abdominal pain
  • Elevated levels of pancreatic enzymes
  • Findings of ultrasonography, CT, MRI

Identification of a heterozygous pathogenic variant in one of the following genes (Table 1) 3, 4:

  • PRSS1 (frequency of pathogenic variants approximately 60%-100% families with hereditary pancreatitis) 1, 9
  • SPINK (3%)1, 10
  • CFTR (11,2%-12,2%) 11, 12
  • CTRC (1%) 10
  • CPA1 (>3,1%) 13

The treatment for pancreatitis can relieve symptoms 1.

  • Pain management
  • Management of maldigestion and diabetes mellitus
  • Total pancreatectomy with islet autotransplantation

Acute pancreatitis:

  • Acute peritonitis
  • Macroamylasemia
  • Macrolipasemia
  • Malabsorption syndromes/processes
  • Perforated viscus

Chronic pancreatitis:

  • Ampullary carcinoma
  • Cholangitis
  • Cholecystitis
  • Chronic gastritis
  • Community-acquired pneumonia (CAP)
  • Crohn disease
  • Intestinal perforation
  • Mesenteric artery ischemia

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Pancreatitis using NGS Panel Genomic:

Step 1: Whole genome sequencing from a single filter card (drop of blood), covering the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Pancreatitis panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified in Step1, continue with bioinformatics analysis covering genes that are either implicated or associated with overlapping phenotype or similar pathways.   

  • Individuals with a positive family history of pancreatitis.
  • Individuals with most common symptoms of pancreatitis (regardless of family history).

Confirmation of a clinical diagnosis through genetic testing of pancreatitis can allow for genetic counseling and may direct medical management.

Overview of genes in Pancreatitis panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
APC 611731 colorectal cancer; Hepatocellular Carcinoma; Desmoid disease, hereditary; familial adenomatous polyposis; Gastric Cancer AD 40
APOA5 606368 AD 1
APOC2 608083 Apolipoprotein C-Ii Deficiency AR 5
ATM 607585 familial breast cancer; ataxia-telangiectasia AD, AR 76
BMPR1A 601299 Juvenile polyposis syndrome AD 9
BRCA1 113705 familial breast-ovarian cancer type 1; pancreatic cancer type 4; Fanconi anemia, complementation group S AD, AR 248
BRCA2 600185 familial breast cancer; Medulloblastoma; Prostate Cancer; Wilms tumor, type 1; Fanconi anemia complementation group D1; familial breast-ovarian cancer type 2; pancreatic cancer type 2 AD, AR 242
CASR 601199 Hypocalciuric hypercalcemia, type I; Hyperparathyroidism, neonatal; Hypocalcemia, autosomal dominant, with Bartter syndrome; Epilepsy idiopathic generalized, susceptibility to, 8 AD, AR 12
CDKN2A 600160 Malignant melanoma 2; Pancreatic cancer/melanoma syndrome AD 8
CFTR 602421 hereditary pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens AD, AR 107
CPA1 114850 14
CTRC 601405 hereditary pancreatitis AD 5
EPCAM 185535 Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8 AR 20
GPIHBP1 612757 Hyperlipoproteinemia, type 1D AR 1
MEN1 613733 multiple endocrine neoplasia type 1 AD 7
MLH1 120436 Muir-Torre syndrome; mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-2 AD, AR 17
MSH2 609309 Lynch syndrome; Muir-Torre syndrome; mismatch repair cancer syndrome AD, AR 27
MSH6 600678 mismatch repair cancer syndrome; endometrial cancer; hereditary nonpolyposis colorectal cancer-5 AD, AR 21
PALB2 610355 familial breast cancer; Fanconi anemia of complementation group N; Pancreatic cancer, susceptibility to, 3 AD 10
PMS2 600259 mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-4 AR 27
PRSS1 276000 hereditary pancreatitis AD, AR 7
SMAD4 600993 Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Pancreatic Cancer AD 3
SPINK1 167790 hereditary pancreatitis AD, AR 7
STK11 602216 Peutz-Jeghers syndrome; Pancreatic Cancer; Spermatocytic seminoma, somatic AD 23
TP53 191170 familial breast cancer; colorectal cancer; Hepatocellular Carcinoma; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD 14
VHL 608537 Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 AD, AR 12