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PTF1A encodes a pancreas-specific helix-loop-helix transcription factor essential for pancreatic progenitor development. Biallelic loss-of-function coding and noncoding variants in PTF1A result in variable pancreatic agenesis without cerebellar involvement, defining a distinct autosomal recessive disorder. Functional and genetic data across multiple cohorts strongly support a causative role for PTF1A in isolated pancreatic agenesis.
In a consanguineous pedigree, homozygous hypomorphic PTF1A missense mutation c.571C>A (p.Pro191Thr) was identified in four probands presenting with neonatal diabetes and exocrine pancreatic insufficiency but normal neurodevelopment ([PMID:27284104]). This variant segregated in two affected sib-pairs and was absent in 259 additional neonatal diabetes cases. Transient transfection assays demonstrated a 75% reduction in transactivation activity of the mutant protein, correlating PTF1A dosage with pancreatic phenotype.
Whole-genome sequencing in ten families uncovered six distinct recessive mutations in a ~400-bp enhancer 25 kb downstream of PTF1A abolishing enhancer activity in hESC-derived pancreatic progenitors—these noncoding variants are the most common cause of isolated pancreatic agenesis ([PMID:24212882]). A subsequent series of 30 patients from 12 referral centers revealed five homozygous enhancer mutations, including a founder Chr10:g.23508437A>G allele in 18 cases, all with neonatal diabetes and exocrine insufficiency; some exhibited anemia, cholestasis, and mild developmental delay ([PMID:32893856]).
Inheritance is autosomal recessive with segregation of homozygous variants in multiple families. Affected relatives (siblings) were documented in three pedigrees with coding variants, and recessive inheritance of enhancer alleles was consistent in 10 families. These findings span at least 44 probands across 12 families, with recurrent founder alleles bolstering genetic evidence.
Functional assays consistently demonstrate that enhancer mutations abolish PTF1A expression in pancreatic progenitors, while the p.Pro191Thr coding change significantly impairs protein transactivation. Concordant mouse model data link Ptf1a dosage to pancreatic development, supporting haploinsufficiency as the mechanism.
Overall, the association between biallelic PTF1A variants and isolated pancreatic agenesis is classified as Strong (44 probands; multi-family segregation; functional concordance). Genetic evidence is Strong (numerous coding and enhancer mutations in 12 families; founder effect). Functional evidence is Moderate (in vitro enhancer and transactivation assays). No conflicting reports have been identified. Key take-home: PTF1A sequencing—including noncoding enhancer regions—should be incorporated into diagnostic panels for neonatal diabetes and isolated pancreatic agenesis to guide clinical management and genetic counseling.
Gene–Disease AssociationStrong44 probands across 12 families with biallelic coding or enhancer PTF1A mutations; segregation in multiple consanguineous pedigrees; functional concordance Genetic EvidenceStrong44 probands from 12 families, including 4 coding and 40 enhancer cases; segregation and recurrent founder variant Functional EvidenceModerateIn vitro enhancer assays show abolished enhancer activity; p.Pro191Thr reduces transactivation by 75% |