A number sign (#) is used with this entry because of evidence that isolated pancreatic agenesis-2 (PAGEN2) is caused by homozygous or compound heterozygous mutation in a distal enhancer of the PTF1A gene (607194) on chromosome 10p12.

Pancreatic agenesis-2 (PAGEN2) is an autosomal recessive disorder characterized by neonatal-onset diabetes mellitus and pancreatic exocrine deficiency (Weedon et al., 2014).

For a discussion of genetic heterogeneity of pancreatic agenesis, see PAGEN1 (260370).

Weedon et al. (2014) reported 14 affected individuals from 10 families with isolated pancreatic hypoplasia or agenesis. Patients were typically diagnosed with insulin-dependent diabetes mellitus at birth or in infancy, although 2 individuals were diagnosed at ages 8 and 10 years, respectively, and 1 at 22 years of age. All patients also had pancreatic exocrine insufficiency, with low or undetectable stool elastase in all who were tested. Pancreatic hypoplasia or agenesis was documented by ultrasound, CT, or MRI in the 9 patients studied. No neurologic features were reported, except for 1 patient who exhibited mild developmental delay, and no other abnormalities were reported, except for 1 patient who had fatal cholestatic liver failure.

The transmission pattern of pancreatic agenesis in the families reported by Weedon et al. (2014) was consistent with autosomal recessive inheritance.

In 6 affected individuals and 1 unaffected family member from 3 unrelated consanguineous families with isolated pancreatic agenesis, Weedon et al. (2014) performed homozygosity mapping that revealed a single shared locus on chromosome 10p12.2-p12.1. Recombination events defined a 6.38-Mb minimal region at chr10:22,526,125-28,843,478 (GRCh37) containing 25 genes, including PTF1A; however, mutations in those genes were excluded by Sanger sequencing.

By whole-genome sequencing of a Syrian and a Lebanese proband, both from multiplex consanguineous families with isolated pancreatic agenesis mapping to chromosome 10p12, Weedon et al. (2014) identified homozygosity for the same variant, a point mutation located about 25 kb downstream of the PTF1A gene within an approximately 400-bp evolutionarily conserved region. Sequencing of this putative pancreatic developmental enhancer in 19 additional probands with PAGEN revealed recessive mutations in 7 of 10 probands with isolated pancreatic agenesis as well as in 1 patient who also had fatal cholestatic liver failure. Overall, 9 affected individuals from 6 unrelated families of Syrian, Lebanese, Kurdish, and Turkish ancestry were homozygous for the same point mutation on chromosome 10, as part of a shared 1.2-Mb haplotype. In addition, a sporadic patient from Pakistan was homozygous and a sporadic patient from Germany compound heterozygous for point mutations in the same region, and 2 Arabian sibs were homozygous for a 7.6-kb deletion that included the entire putative enhancer. Finally, a sporadic Costa Rican patient who had pancreatic agenesis with fatal cholestatic liver failure was homozygous for another point mutation. Testing of parents and sibs demonstrated cosegregation of the mutations with diabetes and exocrine insufficiency, and none of the mutations were found in controls. Functional analysis demonstrated that the approximately 400-bp region acts as a developmental enhancer of PTF1A in human embryonic pancreatic progenitor cells and that the 6 mutations abolish enhancer activity. Amberger (2014) noted that the mutations identified by Weedon et al. (2014) are located within C10ORF115, a long noncoding RNA.