PTF1A – Permanent Neonatal Diabetes Mellitus-Pancreatic and Cerebellar Agenesis Syndrome

PTF1A encodes a basic helix-loop-helix transcription factor essential for pancreatic and cerebellar development. Homozygous loss-of-function alleles in PTF1A classically cause combined pancreatic and cerebellar agenesis with permanent neonatal diabetes. Hypomorphic missense alleles may lead to isolated pancreatic phenotypes without neurologic involvement. The association of PTF1A with Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome is classified as Moderate under ClinGen criteria. This classification reflects 4 affected individuals across two consanguineous pedigrees and concordant functional data (PMID:27284104).

Inheritance is autosomal recessive, evidenced by homozygosity in two inbred families. Genome-wide SNP typing in a consanguineous pedigree localized a 31 Mb homozygous region spanning PTF1A. Sanger sequencing identified a recurrent missense variant c.571C>A (p.Pro191Thr) in two affected siblings, absent in unaffected relatives. Targeted next-generation sequencing of 259 additional neonatal diabetes patients uncovered a second family with the same homozygous allele. All four patients presented with diabetes at birth requiring insulin therapy. Two exhibited exocrine pancreatic insufficiency but none showed cerebellar anomalies (PMID:27284104).

To date, only the single allele c.571C>A (p.Pro191Thr) has been reported in this syndrome. This recurrent hypomorphic variant segregates in a homozygous state within two independent consanguineous pedigrees. No truncating or splice variants have been described in isolated pancreatic agenesis without cerebellar involvement. The allele is absent from population control databases, underscoring its rarity. This expands the PTF1A allelic spectrum to include dosage-sensitive missense changes distinct from classical loss-of-function alleles. The hypomorphic nature correlates with preserved cerebellar development (PMID:27284104).

Functional assessment in transiently transfected HEK293 cells demonstrated a 75 % reduction in PTF1A transactivation activity for the p.Pro191Thr mutant compared to wild-type. This supports a hypomorphic loss-of-function mechanism rather than a complete null effect. Mouse model dose–response data align with the clinical observation that reduced Ptf1a dosage yields isolated pancreatic phenotype. The direct concordance between in vitro severity and human phenotype strengthens pathogenic inference. No rescue assays have been performed to date. Functional data provide mechanistic confirmation of allele pathogenicity (PMID:27284104).

There are no published reports disputing the PTF1A association with neonatal diabetes without cerebellar agenesis. Heterozygous carriers in the reported families show no glucose intolerance or neurologic anomalies. The variant c.571C>A is not present in large population cohorts, minimizing concerns about benign polymorphism. The phenotype is consistent and specific across all homozygotes. Absence of neurodevelopmental delay across four individuals reduces confounding syndromic overlap. No substantive conflicting evidence has emerged.

In summary, homozygous PTF1A c.571C>A (p.Pro191Thr) causes autosomal recessive permanent neonatal diabetes with pancreatic hypoplasia and preserved cerebellar function. Genetic data from four individuals in two pedigrees and in vitro functional assays meet ClinGen criteria for a Moderate gene–disease association. Clinical screening for PTF1A hypomorphic variants should be considered in neonatal diabetes patients lacking cerebellar anomalies. This work highlights the dosage sensitivity of PTF1A in human pancreatic development. Further cohort studies will refine penetrance, expressivity, and potential genotype-phenotype correlations. Key take-home: PTF1A p.Pro191Thr is a clinically actionable biomarker for permanent neonatal diabetes with isolated pancreatic agenesis.

References

• Diabetes | 2016 | Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation. PMID:27284104

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