Endocrine Abstracts

Pseudohypoparathyroidism (PHP) is due to parathyroid hormone (PTH) resistance that results in hypocalcaemia, hyperphosphataemia and elevated plasma PTH concentrations. Some PHP patients also have Albright’s hereditary dystrophy (AHO), which is characterised by short stature, round faces, dental hypoplasia, brachydactyly, subcutaneous ossifications and reduced mental acuity. The 3 major types of PHP referred to as PHP type 1a (PHP1a), PHP1b and pseudopseudohypoparathyroidism (PPHP) may be inherited as autosomal dominant disorders. PHP1a and PPHP are due to mutations of the GNAS1 gene that involve parental imprinting, and PHP1b is due to abnormalities upstream of GNAS1. PHP1a patients have plasma biochemical abnormalities in association with AHO; PHP1b patients have plasma abnormalities only; and PPHP patients have AHO only. Here, we report a GNAS1 mutation (c.348dupC), which is predicted to cause a frame-shift and a premature stop codon p.Val117fs*23, that occurred in a Scottish kindred with 4 siblings affected with PHP1a. Informed consent was obtained using guidelines approved by the local ethical committee. The mutation was not detected by Sanger sequence DNA analysis, but instead was identified by whole genome sequencing (WGS). Other examples of variants identified by WGS, but not traditional sequencing approaches, include patients with Dravet syndrome, hereditary motor and sensory neuropathy type 2 and Charcot-Marie-Tooth type 2C (Landouré et al. 2012 Neurology; Klein et al. 2014 J Neurol Neurosurg Psychiatry; Djemie et al. 2016 Mol Genet & Genome Med). Mutations may not be detected by Sanger DNA sequencing due to technical problems, which include: the mutated peak being too low either due to insufficient dideoxy-chain termination or somatic mosaicism; the mutation being located in a homopolymer stretch; or the design of PCR primers spanning common polymorphisms, thereby leading to mono-allelic amplification. Thus, our results demonstrate that WGS can identify mutations in known causative genes previously not detected by Sanger sequencing.