A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B.

GNAS exons 1-13 encode the biallelically expressed alpha-subunit of the stimulatory G protein (Gαs). Additional transcripts derived from this locus use alternative first exons that undergo parent-specific methylation, thus allowing transcription only from the non-modified allele. Pseudohypoparathyroidism type Ia (PHP1A) is characterized by Albright's Hereditary Osteodystrophy (AHO) and resistance to multiple hormones; this disorder is caused by maternal inactivating mutations involving Gαs exons. In contrast, pseudohypoparathyroidism type Ib (PHP1B) is characterized mostly by resistance to PTH and often mild TSH resistance, usually without AHO features. The autosomal dominant variant of PHP1B (AD-PHP1B) is caused by maternal deletions in GNAS or STX16 that reduce Gαs expression through loss-of-methylation at GNAS exon A/B alone or at multiple differentially methylated regions (DMR). Several large maternal deletions involve not only GNAS exons 1-13, but also one or several GNAS DMRs, thus causing PHP1A combined with apparent GNAS epigenetic changes that are indistinguishable from those observed in PHP1B. Some of these deletions include a large CpG island extending from exon A/B to the intron between GNAS exons 1 and 2, but there is no evidence for parent-specific exon 1 methylation. We now describe a family in which the female proband and her daughter presented with hypocalcemia, elevated PTH levels, shortened metacarpals, and obesity, but without obvious neurocognitive abnormalities. A maternally inherited 2015-bp deletion that includes GNAS exon 1 was identified thereby establishing the diagnosis of PHP1A. The centromeric deletion breakpoint is located 178bp upstream of exon 1, yet no methylation changes were observed at exon A/B. This novel deletion therefore refines further the region between exon A/B and exon 1 that is critical for establishing or maintaining normal methylation at GNAS exon A/B.