Other studies that have used targeted approaches with a limited number of known imprinted DMRs have also reported multi-locus defects in PHP patients.
Though larger cohorts are needed to be conclusive, based on results from both the HM450k and the EpiTYPER study, it seems that PHPneg patients are more sensitive to these multi-locus defects compared to PHPΔstx16 patients.
In addition, mutations in SPT21 appear to cause the same pattern of histone locus transcription defects as do mutations in SPT10 (Dollard et al. 1994; Hess et al. 2004; Sherwood and Osley 1991).
Maupetit-Méhouas et al. studied a larger cohort of 63 PHP patients for the methylation pattern at eight imprinted loci and found multi-locus imprinting defects for 4 PHP patients at PEG1/MEST, L3MBTL1, and DLK1/GTL2 [ 23].
Moreover, as shown for other imprinting disorders, such as Silver-Russell or Beckwith-Wiedemann syndrome, also some PHP1B patients were shown to have multi-locus imprinting defects as studied by a targeted approach that comprised known imprinted loci [ 22– 22].
The other patients with multi-locus methylation defects have no additional clinical or molecular features.
Moreover, a novel GNAS-AS2 DMR affects all PHP patients, and PHP patients seem sensitive to multi-locus methylation defects.
The analysis of 58 DMRs revealed that 8/18 PHPneg and 1/6 patients6 patients have multi-locus methylation defects.
In accordance with previous studies, our PHP patients with multi-locus methylation defects do not show evidence for phenotype differences with patients having only a GNAS methylation defect.
In addition to methylation abnormalities for the 4 GNAS DMRs, we found multi-locus methylation defects in 8 PHPneg and 1 patients6 patients (Fig. 5).
Taking into consideration the genetic component of the PCG, it is possible to observe a strong heterogeneity in terms of disease-associated loci, penetrance defects, and expressivity of the disease among the different populations.
