1. NGS panel - Genetic testing for pancreatitis

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 the genes in CENTOGENE´s pancreatitis panel

Gene (OMIM) Pancreatitis type (Locus) Inheritance Protein % of individuals with pancreatitis
CFTR
(602421)
Idiopathic pancreatitis, Cystic fibrosis
7q31.2
AD, AR Cystic fibrosis transmembrane conductance regulator 11.2% in Australian11, 12,2% in Italian cohort12
CPA1
(114850)
Early onset chronic pancreatitis
7q32.2
unknown Carboxypeptidase A, pancreatic exopeptidase 29/944 (3.1%) German cases and 5/3,938 (0.1%) controls13
CTRC
(601405)
Chronic hereditary pancreatitis
1p36.21
AD Chymotrypsin C R254W mutation found in 0.9% of patients with alcoholic pancreatitis10 
PRSS1
(276000)
Hereditary pancreatitis, Trypsinogen deficiency
7q34
AD, AR Protease serine 1; Trypsinogen 1 60%-100% in hereditary pancreatitis1,9 90% of PRSS1 pathogenic variants include p.Asn29Ile and p.Arg122His9
SPINK1
(167790)
Hereditary pancreatitis, Tropical calcific pancreatitis, susceptibility to Fibrocalculous pancreatic diabetes
5q32
AD, AR Serine protease inhibitor, Kazel-type 1 p.Asn34Ser in 3% of affected in US and Europe1
c.194+2T>C common in China, Japan, and Korea10

More information on CENTOGENE´s pancreatitis panel can be found in our genetic test catalogue.