Submission Details

PDX1 was first reported in relation to autosomal recessive pancreatic agenesis with neonatal diabetes mellitus in 1997 (Stoffers et al., PMID: 8988180). Five variants (missense and frameshift) that have been reported in 4 probands in 4 publications (PMIDs: 8988180, 12970316, 19496967, 20009086) are included in this curation. The mechanism of pathogenicity appears to be LOF through a variety of mechanisms. One variant, c.188del/p.Pro63fs, reported in the homozygous state in at least two patients with neonatal diabetes and pancreatic agenesis (PMIDs: 8988180, 19496967), was shown to create two isoforms, one which is transcriptionally inactive and one which localizes to the nucleus and binds DNA but lacks a transactivation domain (PMID: 9649577). Two missense variants reported in the compound heterozygous state in a patient with diabetes and pancreatic agenesis were shown to reduce levels of the IPF-1 protein encoded by PDX1 (PMID: 12970316). Two cousins with neonatal diabetes without pancreatic agenesis but found to have subclinical evidence of exocrine pancreatic deficiency were homozygous for a missense variant found to reduce PDX1 transactivation (PMID: 20009086). Overall case-level evidence: 8 points. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 15756539, 23715323, 7935793, 8631275). An in vitro functional assay supported the role of PDX1 disruption in impaired proinsulin processing and insulin secretion (PMID: 15756539). PDX1 expression has been confirmed in the pancreas via eQTL analysis (PMID: 23715323). Evidence from 2 mouse models has supported the role of PDX1 disruption in pancreatic agenesis (PMIDs: 7935793, 8631275). Overall experimental evidence 5 points. Overall genetic and experimental evidence 13 points.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, autosomal dominant monogenic diabetes (OMIM:606391) and autosomal recessive pancreatic agenesis 1 with neonatal diabetes (OMIM: 260370). The split curation for autosomal dominant monogenic diabetes has been curated separately.

In summary, PDX1 is definitively associated with autosomal recessive pancreatic agenesis or pancreatic exocrine dysfunction with neonatal diabetes mellitus, particularly through the c.188del variant, which effectively leads to complete loss of function in homozygotes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.