ClinVar

Description

The heterozygous p.Pro65Leu variant in PCGF2 has been identified as de novo in at least four individuals including this patient being tested (PMID: 25533962, DECIPHER database, Broad Institute Rare Genomes Project) with overlapping features of intellectual disability, external ear abnormalities, and dysmorphic features. It is absent from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Additionally, the proline (Pro) at position 65 is highly conserved in mammals and in evolutionarily distant species, suggesting that a change at this position may be disruptive. A mouse model with a complete homozygous knockout of this gene leads to early death of mice, suggesting the gene is critical for humans; however, heterozygotes were normal and no model is available for the Pro65Leu variant which may act through a distinct gain of function mechanism. In summary, with four independent de novo observations of this variant in individuals with overlapping phenotypes, we believe this variant is likely pathogenic for this individual's condition which includes non-verbal intellectual disability, autism, hypotonia, camptodactly, scoliosis, chronic constipation, GERD, mild cortical vision impairment, low set crumpled ears, mildly dilated aorta, and life-threatening food allergies.