Society: AGA

Background
Germline genetic testing is recommended for younger patients with idiopathic pancreatitis, but there is no consensus recommendation for those over age 35. We aimed to analyze the results of genetic testing for pancreatic genetic mutations using a large dataset including all ages.

Methods
Individuals (ages 0-90) who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 for any cause were selected. Test results and information collected from requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel result (defined as at least one pathogenic, likely pathogenic, and/or increased risk variant in a pancreatitis-related gene). Clinically significant results were defined as positive results in PRSS1, biallelic CFTR or SPINK1, or polygenic (i.e., CFTR and CASR).

Results
Overall, 2,468 subjects with primary indication of acute pancreatitis (AP; n=401), chronic pancreatitis (CP; n=631), pancreatic cancer (n=128), or other indications (n=1,308) completed panel testing. Among subjects with AP or CP (n=1,032), the most common variants were monoallelic CFTR (18.8%), monoallelic SPINK (6.9%), PRSS1 (4.5%), polygenic (2.0%), CTRC (1.6%), and biallelic CFTR (1.3%). The frequency of pathogenic variants varied according to age at the time of testing (Figure 1, 2). Variants in CASR contributed to polygenic results (with SPINK1) in 3 subjects. Among patients with pancreatic cancer, 10.2% had monoallelic variants in CFTR, but none had biallelic variants in CFTR.

Among subjects with AP or CP, the frequency of an abnormal result was significantly greater for those <35 versus ≥35 years of age (32.1% vs 24.5%, p=0.007). Similarly, the frequency of a clinically significant result was higher for those <35 vs ≥35 years of age (10.8% vs 5.4%, p=0.001). After adjusting for age, sex, race/ethnicity, primary indication for testing, and family history of pancreatitis, a positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92-25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83-0.95).

Discussion
The yield of germline genetic testing is highest in younger individuals with a positive family history of pancreatitis, which supports current recommendations for testing. However, a clinically significant result was found in approximately 5% of older adults. Therefore, we suggest that genetic counseling and germline testing should be considered for patients of all ages with acute or chronic pancreatitis.

<b>Figure 1:</b> Prevalence of positive pancreatitis panel defined by any positive or positive with clinical implications according to age at the time of germline testing among subjects who completed the multigene pancreatitis panel for a primary indication of acute pancreatitis (AP) or chronic pancreatitis (CP) (n=1,032).

Figure 1: Prevalence of positive pancreatitis panel defined by any positive or positive with clinical implications according to age at the time of germline testing among subjects who completed the multigene pancreatitis panel for a primary indication of acute pancreatitis (AP) or chronic pancreatitis (CP) (n=1,032).

<b>Figure 2:</b> Prevalence of pathogenic variants in pancreatitis-associated genes* according to age at the time of germline testing among subjects who completed the multigene pancreatitis panel for a primary indication of acute pancreatitis (AP) or chronic pancreatitis (CP) (n=1,032). *<i>CASR, CPA1</i> and <i>CTRC</i> are not shown.

Figure 2: Prevalence of pathogenic variants in pancreatitis-associated genes* according to age at the time of germline testing among subjects who completed the multigene pancreatitis panel for a primary indication of acute pancreatitis (AP) or chronic pancreatitis (CP) (n=1,032). *CASR, CPA1 and CTRC are not shown.

Josie Baker

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