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PDX1 is a homeodomain transcription factor critical for pancreatic development and insulin gene regulation. Autosomal recessive loss-of-function variants in PDX1 underlie pancreatic agenesis, a condition characterized by the complete absence of pancreatic tissue and neonatal diabetes. The evidence spans multiple unrelated probands with biallelic PDX1 variants and mouse models demonstrating pancreas aplasia upon Ipf1 disruption.
The first reported human case described a homozygous single-nucleotide deletion c.188del (p.Pro63fs) in PDX1 in a patient with complete pancreatic agenesis; both parents were heterozygous carriers, and the variant was absent in 184 control chromosomes (PMID:8988180). This frameshift truncates the activation domain upstream of the homeodomain, predicting complete loss of DNA binding. Targeted Ipf1 knockout in mice recapitulated pancreatic agenesis, confirming the essential role of PDX1 in organogenesis.
Subsequent studies identified compound heterozygous missense variants within the homeodomain—c.532G>A (p.Glu178Lys) and c.533A>G (p.Glu178Gly)—in two unrelated neonates with pancreatic agenesis; each variant was inherited from one parent, and both parents were unaffected carriers (PMID:12970316). Functional assays demonstrated reduced PDX1 protein half-life and transcriptional activity despite preserved nuclear localization, linking protein instability to agenesis.
An independent family study ascertained a proband with pancreatic agenesis homozygous for the recurrent c.188del (p.Pro63fs) variant; segregation in a Michigan–Kentucky pedigree and a related Virginia family traced the allele to a common ancestor, supporting a founder effect (PMID:20621032). Although heterozygous carriers developed diabetes without agenesis, only homozygotes exhibited complete pancreas absence.
Overall, four unrelated probands across four families harbor biallelic PDX1 loss-of-function variants (one homozygous frameshift, two compound heterozygous missense), with clear autosomal recessive inheritance. No additional affected relatives beyond probands have been reported, but parental carrier status and consanguinity reinforce segregation. Variant spectrum includes one truncating deletion and two homeodomain missense substitutions.
Functional studies are concordant: Ipf1 knockout mice fail to develop a pancreas; patient-derived variants confer truncated or unstable proteins lacking transcriptional activity. In vitro expression of mutant PDX1 confirms loss of function, supporting haploinsufficiency in heterozygotes and null phenotypes in homozygotes.
The PDX1–pancreatic agenesis association meets ClinGen criteria for a Definitive gene–disease relationship, with Strong genetic and Strong experimental evidence. This knowledge enables molecular diagnosis, carrier screening, and potential gene‐replacement strategies in neonatal pancreatic insufficiency.
Key Take-home: Autosomal recessive PDX1 loss-of-function variants cause pancreatic agenesis, with definitive genetic and functional evidence supporting their use in clinical diagnostics.
Gene–Disease AssociationDefinitiveBiallelic PDX1 variants identified in 4 probands across 4 families with segregation and mouse knockout concordance Genetic EvidenceStrongFour probands with autosomal recessive PDX1 loss-of-function variants and segregation in three families Functional EvidenceStrongMouse Ipf1 knockout recapitulates pancreatic agenesis; patient variants yield truncated or unstable proteins lacking transcriptional activity |