RESEARCH ARTICLE Pseudohypoparathyroidism Type Ib Associated with Novel Duplications in the GNAS Locus

Context Pseudohypoparathyroidism type 1b (PHP-Ib) is characterized by renal resistance to PTH (and, sometimes, a mild resistance to TSH) and absence of any features of Albright's hered-itary osteodystrophy. Patients with PHP-Ib suffer of defects in the methylation pattern of the complexGNAS locus. PHP-Ib can be either sporadic or inherited in an autosomal dominant pattern. Whereas familial PHP-Ib is well characterized at the molecular level, the genetic cause of sporadic PHP-Ib cases remains elusive, although some molecular mechanisms have been associated with this subtype. Objective The aim of the study was to investigate the molecular and imprinting defects in theGNAS locus in two unrelated patients with PHP-Ib. Design We have analyzed the GNAS locus by direct sequencing, Methylation-Specific Multiplex Li-gation-dependent Probe Amplification, microsatellites, Quantitative Multiplex PCR of Short Fluorescent fragments and array-Comparative Genomic Hybridization studies in order to characterize two unrelated families with clinical features of PHP-Ib. Results We identified two duplications in theGNAS region in two patients with PHP-Ib: one of them, comprising*320 kb, occurred ‘de novo ’ in the patient, whereas the other one, of*179 kb in length, was inherited from the maternal allele. In both cases, no other known genetic cause was observed