{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:39:35Z","timestamp":1760060375084,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM)"},{"name":"Association des Pancr\u00e9atites Chroniques H\u00e9r\u00e9ditaires"},{"name":"Association Ga\u00e9tan Sale\u00fcn, France"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: While complete loss-of-function (LoF) SPINK1 variants in the simple heterozygous state cause chronic pancreatitis, biallelic complete LoF variants result in a rare pediatric disorder termed severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null SPINK1 genotype have been reported\u2014one homozygous for a whole-gene deletion and the other for an Alu insertion in the 3\u2032 untranslated region. Here, we report the genetic basis of a third SIIEPI case, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis. Methods: Targeted next-generation sequencing (NGS) was used to analyze the entire coding region and exon\u2013intron boundaries of the SPINK1 gene. Copy number variant (CNV) analysis was performed with SeqNext, based on normalized amplicon coverage. Results: The proband harbored compound heterozygous complete LoF SPINK1 variants. One was the known NM_001379610.1:c.180_181del (p.(Cys61PhefsTer2)), inherited from the father. The second, initially detected as an exon 2 deletion and confirmed by quantitative fluorescent multiplex PCR (QFM-PCR), was further characterized by long-range PCR as a complex rearrangement comprising a 1185 bp deletion removing exon 2, a 118 bp templated insertion followed by a non-templated nucleotide, and an 8 bp deletion. The mutational signature is consistent with serial replication slippage or template switching involving translesion synthesis. This maternally inherited variant has not been previously reported. Conclusions: This study expands the mutational spectrum of SPINK1-related SIIEPI and suggests that this distinct pediatric disorder may be under recognized in clinical practice.<\/jats:p>","DOI":"10.3390\/genes16090998","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:26:31Z","timestamp":1756189591000},"page":"998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Compound Heterozygous Complete Loss-of-Function SPINK1 Variants as a Novel Cause of Severe Infantile Isolated Exocrine Pancreatic Insufficiency"],"prefix":"10.3390","volume":"16","author":[{"given":"Emmanuelle","family":"Masson","sequence":"first","affiliation":[{"name":"Inserm, Univ Brest, EFS, UMR 1078, GGB, 29200 Brest, France"},{"name":"Service de G\u00e9n\u00e9tique M\u00e9dicale et de Biologie de la Reproduction, CHU Brest, 29200 Brest, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Wangermez","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, Poitiers University Hospital, 86000 Poitiers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8065-9635","authenticated-orcid":false,"given":"David","family":"Tougeron","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, Poitiers University Hospital, 86000 Poitiers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinciane","family":"Rebours","sequence":"additional","affiliation":[{"name":"Pancreatology and Digestive Oncology Department, Beaujon Hospital, APHP\u2014Clichy, Universit\u00e9 Paris Cit\u00e9, 75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claude","family":"F\u00e9rec","sequence":"additional","affiliation":[{"name":"Inserm, Univ Brest, EFS, UMR 1078, GGB, 29200 Brest, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2424-3969","authenticated-orcid":false,"given":"Jian-Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Inserm, Univ Brest, EFS, UMR 1078, GGB, 29200 Brest, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/0006-291X(85)91176-3","article-title":"Molecular cloning and nucleotide sequence of human pancreatic secretory trypsin inhibitor (PSTI) cDNA","volume":"132","author":"Yamamoto","year":"1985","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/0006-291X(87)90415-3","article-title":"Primary structure of human pancreatic secretory trypsin inhibitor (PSTI) gene","volume":"149","author":"Horii","year":"1987","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/BF01318373","article-title":"Effects of chronic alcohol abuse on exocrine pancreatic secretion in man","volume":"30","author":"Rinderknecht","year":"1985","journal-title":"Dig. Dis. Sci."},{"key":"ref_4","unstructured":"Go, V.L.W., Dimagno, E.P., Gardner, J.D., Lebenthal, E., and Scheele, G.A. (1993). Pancreatic secretory enzymes. The Pancreas: Biology, Pathobiology, and Disease, Raven Press."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/76088","article-title":"Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis","volume":"25","author":"Witt","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"G518","DOI":"10.1152\/ajpgi.00431.2009","article-title":"Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype","volume":"298","author":"Romac","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1053\/j.gastro.2004.11.052","article-title":"Transgenic expression of pancreatic secretory trypsin inhibitor-I ameliorates secretagogue-induced pancreatitis in mice","volume":"128","author":"Nathan","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sakata, K., Araki, K., Nakano, H., Nishina, T., Komazawa-Sakon, S., Murai, S., Lee, G.E., Hashimoto, D., Suzuki, C., and Uchiyama, Y. (2016). Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome. Sci. Rep., 6.","DOI":"10.1038\/srep37200"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1136\/gutjnl-2023-330788","article-title":"Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice","volume":"73","author":"Wang","year":"2024","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/ng1096-141","article-title":"Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene","volume":"14","author":"Whitcomb","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1038\/ng1904","article-title":"Hereditary pancreatitis caused by triplication of the trypsinogen locus","volume":"38","author":"Masson","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11227","DOI":"10.1073\/pnas.0703714104","article-title":"Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: Identity with Rinderknecht\u2019s enzyme Y","volume":"104","author":"Szmola","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","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_14","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_15","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1007\/s10620-017-4601-3","article-title":"Genetic risk in chronic pancreatitis: The trypsin-dependent pathway","volume":"62","author":"Hegyi","year":"2017","journal-title":"Dig. Dis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40246-022-00407-x","article-title":"Expanding ACMG variant classification guidelines into a general framework","volume":"16","author":"Masson","year":"2022","journal-title":"Hum. Genomics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40246-025-00740-x","article-title":"Genetics and clinical implications of SPINK1 in the pancreatitis continuum and pancreatic cancer","volume":"19","author":"Wang","year":"2025","journal-title":"Hum. Genomics"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, Y.C., Masson, E., Wang, Q.W., G\u00e9nin, E., Le Gac, G., Fichou, Y., Cooper, D.N., Liao, Z., F\u00e9rec, C., and Zou, W.B. (2025). SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity and classificatory challenges. Am. J. Hum. Genet.","DOI":"10.1016\/j.ajhg.2025.07.013"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1002\/humu.23343","article-title":"Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene","volume":"38","author":"Venet","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1016\/j.ajhg.2024.08.016","article-title":"Alu insertion-mediated dsRNA structure formation with pre-existing Alu elements as a disease-causing mechanism","volume":"111","author":"Masson","year":"2024","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.gastro.2005.05.057","article-title":"Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice","volume":"129","author":"Ohmuraya","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101361","DOI":"10.1016\/j.jcmgh.2024.05.009","article-title":"Heterozygous Spink1 deficiency promotes trypsin-dependent chronic pancreatitis in mice","volume":"18","year":"2024","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.ebiom.2019.09.032","article-title":"Natural history of SPINK1 germline mutation related-pancreatitis","volume":"48","author":"Muller","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s40246-024-00586-9","article-title":"Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possible SPINK1 coding variants","volume":"18","author":"Wu","year":"2024","journal-title":"Hum. Genomics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/s13073-024-01421-5","article-title":"HGVS Nomenclature 2024: Improvements to community engagement, usability, and computability","volume":"16","author":"Hart","year":"2024","journal-title":"Genome Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ymgme.2007.06.006","article-title":"Co-inheritance of a novel deletion of the entire SPINK1 gene with a CFTR missense mutation (L997F) in a family with chronic pancreatitis","volume":"92","author":"Masson","year":"2007","journal-title":"Mol. Genet. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D1313","DOI":"10.1093\/nar\/gkae1090","article-title":"ClinVar: Updates to support classifications of both germline and somatic variants","volume":"53","author":"Landrum","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D383","DOI":"10.1093\/nar\/gkq1170","article-title":"Non-B DB: A database of predicted non-B DNA-forming motifs in mammalian genomes","volume":"39","author":"Cer","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.semcancer.2010.05.007","article-title":"Genomic rearrangements in inherited disease and cancer","volume":"20","author":"Chen","year":"2010","journal-title":"Semin. Cancer Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/humu.20202","article-title":"Complex gene rearrangements caused by serial replication slippage","volume":"26","author":"Chen","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.cell.2007.11.037","article-title":"A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders","volume":"131","author":"Lee","year":"2007","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1002\/humu.22831","article-title":"Complex multiple-nucleotide substitution mutations causing human inherited disease reveal novel insights into the action of translesion synthesis DNA polymerases","volume":"36","author":"Chen","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.biochi.2023.07.002","article-title":"Non-B DNA structures as a booster of genome instability","volume":"214","author":"Duardo","year":"2023","journal-title":"Biochimie"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/sj.ejhg.5201684","article-title":"Detection of a large genomic deletion in the pancreatic secretory trypsin inhibitor (SPINK1) gene","volume":"14","author":"Masson","year":"2006","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41572-024-00538-6","article-title":"Cystic fibrosis","volume":"10","author":"Mall","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s12020-023-03512-6","article-title":"Clinical and genetic characteristics of CEL-MODY (MODY8): A literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes","volume":"83","author":"Sun","year":"2024","journal-title":"Endocrine"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Scheers, I., and Berardis, S. (2022). Congenital etiologies of exocrine pancreatic insufficiency. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.909925"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1755-8417-1-4","article-title":"Mechanisms for human genomic rearrangements","volume":"1","author":"Gu","year":"2008","journal-title":"PathoGenetics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrc2998","article-title":"DNA polymerases and cancer","volume":"11","author":"Lange","year":"2011","journal-title":"Nat. Rev. Cancer"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/998\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:32:30Z","timestamp":1760034750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/9\/998"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["genes16090998"],"URL":"https:\/\/doi.org\/10.3390\/genes16090998","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,8,25]]}}}