PAN2

Inheritance Pattern: AR

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015159

Submitter: King Faisal Specialist Hospital and Research Center

PAN2 was first reported in relation to Autosomal recessive form of syndromic neurodevelopmental disorder and multiple congenital anomalies in 2018 (Maddirevula S, et al., 2018, PMID: 29620724). At least 4 unique variants (e.g. indels, splice variant and nonsense) have been reported in humans with similar phenotype. Variants in this gene have been reported in at least 6 affected in 2 publications (PMID: 29620724; PMID: 35304602). Mice homozygous for an ENU-induced allele exhibit embryonic lethality (MGI:1918984). No convincing contradictory evidence has emerged. Two publications with convincing evidence and no convincing contradictory evidence classified PAN2 as definitive. Gene is scored according to ClinGen classification.

Inheritance Pattern: AR

Disease ID:MONDO:0800439

Submitter: ClinGen

*PAN2* is located on chromosome 12 at 12q13.3 and encodes the Pabp-dependent poly(a) nuclease 2, a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. *PAN2* was first reported in connection with autosomal recessive syndromic complex neurodevelopmental disorder in 2018 (Maddirevula et al., 2018 PMID: 29620724). This disease is characterized by mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (e.g., tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck (PMID: 35304602). Five variants (1 nonsense, 1 duplication, 1 canonical splice-site, 1 frameshift, 1 missense) reported in 5 families have been included in this curation (PMIDs: 35304602, 29620724, 40491293). The mechanism of pathogenicity appears to be loss of function. The patient identified with the homozygous missense variant presented with a less severe clinical condition compared to those reported with truncating mutations. Additionally, one patient reported with a dual diagnosis of glycogen storage disease type IB and syndromic complex neurodevelopmental disorder was excluded from the final genetic evidence score (PMID: 35304602). This gene-disease relationship is supported by relevant experimental evidence, specifically biochemical evidence demonstrating *PAN2*’s function in deadenylation, mRNA stability, and exoribonuclease activity (PMID: 24872509). In summary, there is moderate evidence to support the gene-disease relationship between *PAN2* and autosomal recessive syndromic complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the Syndromic Disorders Gene Curation Expert Panel on August 6th, 2025 (SOP Version 11).