Simultaneous Hyper- and Hypomethylation at Imprinted Loci in a Subset of Patients withGNASEpimutations Underlies a Complex and Different Mechanism of Multilocus Methylation Defect in Pseudohypoparathyroidism Type 1b

Abstract

Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell-Silver or Beckwith-Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", that is, the phenotype is controlled by the most severely affected imprinted locus.

European guidance for the molecular diagnosis of pseudohypoparathyroidism not caused by point genetic variants at GNAS: an EQA study

“…Partial methylation defects may arise from a postzygotic occurrence of the epigenetic defect. 19 The distribution of mosaic genetic defects can vary widely among different tissues of a patient, and similar discrepancies can also be found for methylation defects. 43 This implies that partial 'epimutations' detected in lymphocytes of PHP patients might be explained by mosaicism; thus, strict methylation cutoff values for partial GoM or LoM are not useful in this condition.…”

“…5); partial methylation defects at the whole GNAS locus either due to a mosaic of pat20qUPD (EQA no. 8; Maupetit-Mehouas et al 19 ) or from unknown origin (EQA nos. 3, 6 and 7).…”

“…14,15 In a small subset of these patients (10-25% according to various reports), uniparental disomy of chromosome 20q has been identified as the cause of the GNAS methylation anomaly. [16][17][18][19] On the other hand, some cases are familial with an autosomal dominant mode of inheritance (AD-PHP1B). 10 AD-PHP1B is typically associated with a loss of methylation restricted to the exon A/B DMR owing to maternally inherited microdeletions within STX16 11,13,20,21 or NESP55, 22 which likely harbour a cis-acting control element crucial for the establishment of the methylation imprint at exon A/B.…”

Clinical utility gene card for: Transient Neonatal Diabetes Mellitus, 6q24-related

“…[3][4][5][6][7] Copy number imbalance can be detected by MS-MLPA, short tandem repeat marker typing and molecular karyotyping (SNP array, aCGH), and in the case of rare large duplications, FISH or cytogenetic analysis. Uniparental disomy analysis can be performed by short tandem repeat marker typing or by molecular karyotyping using SNP array (UPD testing should preferentially include the parents for full informativity).…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Early-onset obesity Beckwith-Wiedemann syndrome 104,210 Hemihypertrophy and macroglossia Genetic, cytogenetic or syndromic anomalies associated with early-onset obesity , including Prader-Willi syndrome and monogenic obesity (mutations in POMC, MC4R, leptin and the leptin receptor) 46,275 Progression of obesity through childhood; possible associated features, such as red hair and hypoadrenalism…”