Submission Details

PDX1: Monogenic diabetes, autosomal dominant (MONDO: 0015967)

Moderate

PDX1 was first reported in relation to autosomal dominant monogenic diabetes in 1997 (Stoffers et al., 1997). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Variants in this gene have been reported in at least 13 probands in 9 publications. These include three probands heterozygous for the c.188del/p.Pro63fs variant (PMIDs: 9326926, 28436541, 31595705), which 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 and thus behaves as a null or possibly dominant negative variant (PMID: 9649577). Homozygosity for c.188del/p.Pro63fs causes pancreatic agenesis and neonatal diabetes in the homozygous state (PMIDs: 8988180, 19496967). The other probands had missense variants (PMIDs: 10720084, 10545530, 31595705, 33746035, 26226118, 25041077, 31333579), of which five were too common in gnomAD to cause monogenic diabetes (PMIDs 10720084, 10545530, 26226118, 31333579).
Summary of case-level data: 5.2 points. Notably, heterozygous parents of individuals with pancreatic agenesis with neonatal diabetes due to homozygosity or compound heterozygosity for a PDX1 missense variant do not consistently have diabetes (PMIDs: 12970316, 200009086), and thus the role of missense PDX1 variants in autosomal dominant monogenic diabetes is unclear. The c.188del/p.Pro63fs variant segregated with diabetes in 10 meioses in 1 family (LOD = 3.43, 1 point). Total score for genetic evidence: 6.2 points. Evidence from 2 mouse models has supported the role of PDX1 disruption in impaired glucose-stimulated insulin secretion and impaired glucose tolerance (PMIDs: 11781323, 9637677). 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 vis eQTL analysis (PMID: 23715323). Summary of experimental data: 5 points. Total score for genetic evidence and experimental evidence: 11.2 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, monogenic diabetes (OMIM:606391) and pancreatic agenesis with neonatal diabetes (OMIM:260370). The split curation for pancreatic agenesis with neonatal diabetes mellitus has been curated separately.

In summary, there is moderate evidence to support the relationship between PDX1 and autosomal dominant monogenic diabetes, in particular the c.188del/p.Pro63fs variant which creates two functionally inactive isoforms. Missense variants should be interpreted with caution.