CEL

Inheritance Pattern: Unknown

Disease ID:MONDO:0012348

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012348

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012348

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012348

Submitter: ClinGen

*CEL* was first reported in relation to diabetes and exocrine pancreatic dysfunction, including fecal elastase deficiency, in 2002 (Raeder et al., PMID: 16369531) in two probands/families with single base deletion frameshift variants in the first and fourth repeats in the VNTR region of the final exon of the gene. Three additional cases with single base deletion frameshift variants in the first, fourth, and fifth repeats and a diabetes and exocrine pancreatic phenotype have been reported (PMIDs: 34850019, 33417713) (7.5 points total for case-level data). While *CEL* variants have been reported in several other individuals evaluated for isolated monogenic diabetes (PMIDs: 27810688, 19760265, 30012629, 35082198), scoring for these variants was reduced due to limited population data (3 VNTR repeat), high population frequency, inability to confirm by Sanger sequencing, or otherwise limited evidence. Notably, a recent study systematically evaluating *CEL* and 17 other syndromic and 9 nonsyndromic monogenic diabetes genes in 1,280 cases of suspected MODY yielded no *CEL* variants (PMID: 34789499). In the larger of the two diabetes and pancreatic dysfunction families originally reported by Ræder et al (PMID 16369531), the variant segregated with diabetes (14 individuals with mean age of diagnosis of 36 +/- 10 years) with a LOD score of 4.47 (1 point) and with fecal elastase deficiency with a LOD score of 11.6. The families have been extensively studied, showing that children with the variants have been found to have pancreatic lipomas prior to diabetes onset (PMID: 17259390) and that pancreatic cysts and upregulated mitogen-activated protein kinase (MAPK) signaling develop in conjunction with diabetes (PMID: 24062244). Experimental data, including expression studies and cell culture models, added an additional 2 points (PMIDs: 23715323, 24309898, 21784842, 27650499). Evidence supporting this gene-disease relationship includes case level data, segregation data, and experimental data. Summary of genetic and experimental evidence: 10.5 points. The mechanism for disease is currently unknown, but based on molecular studies and the location of pathogenic variants reported to date, evidence for abnormal CEL protein aggregation due to disrupted O-glycosylation potential has been reported as a possible pathogenic mechanism (PMIDs: 21784842, 27650499). In summary, *all cases of monogenic diabetes convincingly attributed to this gene have been single base deletions in the proximal VNTR repeats that alter and shorten the VNTR repeat region and lead to the rare syndrome of autosomal dominant diabetes with exocrine pancreatic dysfunction with measurable fecal elastase deficiency or hereditary pancreatitis*. Importantly, next-generation sequencing may not reliably detect these variants because of the repetitive nature of the region, and the use of long-range PCR in a laboratory familiar with this gene is highly recommended. Taken together, there is a moderate level of evidence for single base deletion frameshift variants in the proximal VNTR repeat region in this gene as causal for the rare disorder of diabetes and exocrine pancreas dysfunction. With careful exocrine pancreatic phenotyping and proper genotyping methodology applied to future suspected cases, it is expected that additional cases will be identified and increase confidence in this assertion.