Clinical utility gene card for: pseudohypoparathyroidism.

Abstract

1.5 Mutational spectrum In E70–80% of cases, PHP-Ia is caused by haploinsufficiency because of maternally-inherited heterozygous inactivating mutations of GNAS gene1,2 (personal data). In very few cases, large deletions including part or the whole gene have been reported,3,4 while in a further subset of patients cytosine methylation defects of the GNAS promoters have been identified, a pattern typically found in PHP-Ib.5–8 Patients affected with PHP-Ib share a loss of methylation on the maternal A/B exon of GNAS. Those with the autosomal dominant form of PHP-Ib (AD-PHP-Ib) display an isolated loss of methylation at exon A/B associated with a recurrent 3-kb deletion in the STX16 gene, although a 4.4-kb deletion has been described in one family with AD-PHP-Ib.9,10 In four families with AD-PHP-Ib, NESP55 and NESPAS deletions have also been described leading to the loss of all maternal GNAS imprints (epimutations).11–13 In most cases, PHP-Ib is sporadic, and is characterized by complete loss of methylation at the NESPas, XLas and A/B promoters, and no other changes in cisor trans-acting elements have been found to explain this loss of methylation. In some cases (2–20% of the patients with PHP-Ib) paternal 20q disomies have been described.14–17