{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:17:46Z","timestamp":1760059066085,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Chronic pancreatitis (CP) is a progressive inflammatory condition of the pancreas that leads to irreversible changes in pancreatic structure. The pancreatic \u03b1 and \u03b2 cells secrete hormones such as insulin and glucagon into the bloodstream. The pancreatic acinar cells secrete digestive enzymes that break down macromolecules. When these digestive enzymes do not function properly, maldigestion, malabsorption, and malnutrition may result. Presented here is a case study of an individual newly diagnosed with chronic pancreatitis, along with a genetic analysis of his son and an in-silico analysis of two of the variant proteins. Methods: This study was conducted using human subjects, namely, the proband (father) and his son. Medical genetic testing of the proband (father) identified the presence of two variants in the cystic fibrosis transmembrane receptor gene (CFTR): variant rs213950, resulting in a single amino acid change (p. Val470Met), and variant rs74767530, a nonsense variant (Arg1162Ter) with known pathogenicity for cystic fibrosis. Medical testing also revealed an additional missense variant, rs515726209 (Ala73Thr), in the CTRC gene. Cheek cell DNA was collected from both the proband and his son to determine the inheritance pattern and identify any additional variants. A variant in the human leukocyte antigen (rs7454108), which results in the HLA-DQ8 haplotype, was examined in both the proband and his son due to its known association with autoimmune disease, a condition also linked to chronic pancreatitis. In silico tools were subsequently used to examine the impact of the identified variants on protein function. Results: Heterozygosity for all variants originally identified through medical genetic testing was confirmed in the proband and was absent in the son. Both the proband and his son were found to have the DRB1*0301 (common) haplotype for the HLA locus. However, the proband was also found to carry a linked noncoding variant, rs2647088, which was absent in the son. In silico analysis of variant rs213950 (Val470Met) in CFTR and rs515726209 (Ala73Thr) in CTRC revealed distinct changes in predicted ligand binding for both proteins, which may affect protein function and contribute to the development of CP. Conclusions: This case study of a proband and his son provides additional evidence for a polygenic inheritance pattern in CP. The results also highlight new information on the role of the variants on protein function, suggesting additional testing of ligand binding for these variants should be done to confirm the functional impairments.<\/jats:p>","DOI":"10.3390\/genes16050603","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T06:10:46Z","timestamp":1747721446000},"page":"603","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Study: Genetic and In Silico Analysis of Familial Pancreatitis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0693-138X","authenticated-orcid":false,"given":"Yash","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Virginia Tech, Blacksburg, VA 24060, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0136-0975","authenticated-orcid":false,"given":"Deborah J.","family":"Good","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA 24060, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S0140-6736(20)31318-0","article-title":"Chronic pancreatitis","volume":"396","author":"Beyer","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1001\/jama.2019.19411","article-title":"Diagnosis and Management of Chronic Pancreatitis: A Review","volume":"322","author":"Singh","year":"2019","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ramsey, M.L., Heald, B., Gokun, Y., Baker, J., Groce, J.R., Han, S., Hart, P.A., Krishna, S.G., Lara, L.F., and Lee, P.J. (2024). Germline multigene panel testing in acute and chronic pancreatitis. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0307076"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"D789","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM.org: Online Mendelian Inheritance in Man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"Amberger","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.1002\/ajmg.a.62407","article-title":"Online Mendelian Inheritance in Man (OMIM\u00ae): Victor McKusick\u2019s magnum opus","volume":"185","author":"Hamosh","year":"2021","journal-title":"Am. J. Med. Genet. Part A."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project","volume":"45","author":"Consortium","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rausch, T., Fritz, M.H., Untergasser, A., and Benes, V. (2020). Tracy: Basecalling, alignment, assembly and deconvolution of sanger chromatogram trace files. BMC Genom., 21.","DOI":"10.1186\/s12864-020-6635-8"},{"key":"ref_8","unstructured":"Kitts, A., Phan, L., Ward, M., and Holmes, J.B. (2025, April 20). The Database of Short Genetic Variation (dbSNP), Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK174586\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"D243","DOI":"10.1093\/nar\/gkae1038","article-title":"NCBI RefSeq: Reference sequence standards through 25 years of curation and annotation","volume":"53","author":"Goldfarb","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"W276","DOI":"10.1093\/nar\/gkac240","article-title":"Search and sequence analysis tools services from EMBL-EBI in 2022","volume":"50","author":"Madeira","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"W408","DOI":"10.1093\/nar\/gkz322","article-title":"IntFOLD: An integrated web resource for high performance protein structure and function prediction","volume":"47","author":"McGuffin","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Roche, D.B., Tetchner, S.J., and McGuffin, L.J. (2011). FunFOLD: An improved automated method for the prediction of ligand binding residues using 3D models of proteins. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-160"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"W303","DOI":"10.1093\/nar\/gkt498","article-title":"The FunFOLD2 server for the prediction of protein-ligand interactions","volume":"41","author":"Roche","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"W431","DOI":"10.1093\/nar\/gkab314","article-title":"Mol* Viewer: Modern web app for 3D visualization and analysis of large biomolecular structures","volume":"49","author":"Sehnal","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W306","DOI":"10.1093\/nar\/gki375","article-title":"I-Mutant2.0: Predicting stability changes upon mutation from the protein sequence or structure","volume":"33","author":"Capriotti","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1002\/prot.20810","article-title":"Prediction of protein stability changes for single-site mutations using support vector machines","volume":"62","author":"Cheng","year":"2006","journal-title":"Proteins"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D33","DOI":"10.1093\/nar\/gkad1044","article-title":"Database resources of the National Center for Biotechnology Information","volume":"52","author":"Sayers","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1089\/gtmb.2019.0199","article-title":"The Cystic Fibrosis Transmembrane Conductance Regulator 470 Met Allele Is Associated with an Increased Risk of Chronic Pancreatitis in Both Asian and Caucasian Populations: A Meta-Analysis","volume":"24","author":"Zhou","year":"2020","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00439-007-0459-3","article-title":"Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis","volume":"123","author":"Masson","year":"2008","journal-title":"Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/mt.2016.112","article-title":"Long Non-coding RNA BGas Regulates the Cystic Fibrosis Transmembrane Conductance Regulator","volume":"24","author":"Saayman","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1093\/nar\/29.1.308","article-title":"dbSNP: The NCBI database of genetic variation","volume":"29","author":"Sherry","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1056\/NEJMra061200","article-title":"Autoimmune pancreatitis","volume":"355","author":"Finkelberg","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.cgh.2007.06.002","article-title":"Risk of pancreatitis in 14,000 individuals with celiac disease","volume":"5","author":"Ludvigsson","year":"2007","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2424470122","DOI":"10.1073\/pnas.2424470122","article-title":"Protein interactions, calcium, phosphorylation, and cholesterol modulate CFTR cluster formation on membranes","volume":"122","author":"Wan","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chin, S., Ramjeesingh, M., Hung, M., Ereno-Oreba, J., Cui, H., Laselva, O., Julien, J.P., and Bear, C.E. (2019). Cholesterol Interaction Directly Enhances Intrinsic Activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Cells, 8.","DOI":"10.3390\/cells8080804"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"L476","DOI":"10.1152\/ajplung.00262.2006","article-title":"Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis","volume":"292","author":"White","year":"2007","journal-title":"Am. J. Physiol. Lung. Cell. Mol. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/0006-291X(72)90300-2","article-title":"The binding of calcium by chymotrypsinogen A","volume":"49","author":"Osborne","year":"1972","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1056\/NEJM199809033391001","article-title":"Mutations of the cystic fibrosis gene in patients with chronic pancreatitis","volume":"339","author":"Sharer","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"842","DOI":"10.5009\/gnl15484","article-title":"Sensitization to and Challenge with Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis","volume":"10","author":"Moon","year":"2016","journal-title":"Gut Liver"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1136\/jmg.29.8.558","article-title":"Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease","volume":"29","author":"Gasparini","year":"1992","journal-title":"J. Med. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0888-7543(91)90500-E","article-title":"The search for south European cystic fibrosis mutations: Identification of two new mutations, four variants, and intronic sequences","volume":"10","author":"Gasparini","year":"1991","journal-title":"Genomics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1074\/jbc.272.2.709","article-title":"Correction of defective protein kinesis of human P-glycoprotein mutants by substrates and modulators","volume":"272","author":"Loo","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1042\/BJ20070478","article-title":"Additive effect of multiple pharmacological chaperones on maturation of CFTR processing mutants","volume":"406","author":"Wang","year":"2007","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/ng.2007.44","article-title":"Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis","volume":"40","author":"Rosendahl","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2725","DOI":"10.1111\/bph.16341","article-title":"Chymotrypsin activity signals to intestinal epithelium by protease-activated receptor-dependent mechanisms","volume":"181","author":"Guignard","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1136\/gutjnl-2012-303090","article-title":"Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk","volume":"62","author":"Beer","year":"2013","journal-title":"Gut"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1111\/bph.15709","article-title":"A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR","volume":"179","author":"Liu","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.coph.2017.09.015","article-title":"CFTR potentiators: From bench to bedside","volume":"34","author":"Jih","year":"2017","journal-title":"Curr. Opin. Pharmacol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/5\/603\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:35:41Z","timestamp":1760031341000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/5\/603"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["genes16050603"],"URL":"https:\/\/doi.org\/10.3390\/genes16050603","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,5,20]]}}}