Figure 6. PHP1B categories based on pathogenic mechanisms and corresponding GNAS methylation patterns.

Patients with PHP1B are classified into 3 categories based on GNAS methylation patterns. Category 1 is characterized by broad methylation defects caused by undetermined underlying causes (sporadic) with the exception of paternal uniparental disomy of chromosome 20 (UPDpat) and deletions comprising the NESP55-AS exons 3/4 region. Category 2 cases show a loss of methylation at AS2 and A/B while AS and XL methylation levels are preserved. Transcriptional attenuation of NESP55 centromeric (upstream) of the AS2 DMR causes this pattern, in which maternal STX16 deletions are the most frequent cause. Category 3 is characterized by isolated A/B loss of methylation with preserved AS2 methylation levels, suggesting that NESP55 transcription is blunted telomeric (downstream) of the AS2 DMR. Asterisk indicates apparent hypomethylation due to copy number gain.