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Endocrine Abstracts (2015) 39 OC5.2 | DOI: 10.1530/endoabs.39.OC5.2

BSPED2015 ORAL COMMUNICATIONS Oral Communications 5 (10 abstracts)

Genetic characterisation of children with short stature and GH or IGF1 insensitivity by single gene and whole exome sequencing

Lucy Shapiro , Martin Savage , Lou Metherell & Helen Storr


Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK.


Background: GH insensitivity (GHI) encompasses growth failure, low serum IGF1 and normal/elevated serum GH. IGF1 insensitivity results in pre- and postnatal growth failure with normal/relatively high IGF1 levels.

Objective: To undertake candidate gene (CGS) and whole exome (WES) sequencing to obtain a genetic diagnosis in children with short stature and GHI or IGF1 insensitivity.

Methods: As a referral centre for GHI genetics, since 2008, we have received DNA samples from 106 children (58M) with short stature (mean height −4.04 SDS, range −9.37 to −0.6 SDS) and normal/high GH. 100 patients had GHI (mean IGF1 −2.53 SDS; range −8.2 to −0.25) and six had IGF1 insensitivity (mean IGF1 2.36 SDS; range 0.6 to 4.4 SDS). CGS was undertaken followed by WES in unsolved cases. WES has been completed in 39 patients and five relatives.

Results: CGS identified homozygous mutations in the following genes in 27 patients: GHR (21), IGFALS (3), OBSL1 (2), CUL7 (1), and heterozygous mutations in three patients: STAT5B (1) and IGF1R (2). Carrier status was confirmed in eight relatives (seven in IGFALS and one in GHR). WES identified mutations in genes known to cause short stature in 11 patients: compound heterozygous IGFALS (1), homozygous GHR (5), heterozygous PTPN11 (2), homozygous CCDC8 (2), and heterozygous SOS1 (1). WES also identified changes in 22 novel, putative candidate genes in 16 patients.

Conclusions: A genetic diagnosis was obtained in 39% (41/106) of patients, whose DNA was sent for investigation. 73% were determined by CGS and 27% by WES. As well as identifying mutations in other candidate genes, WES also identified mutations in the GHR and IGFALS genes, which had not been detected on CGS. Diagnoses with similar phenotypes included SRS, Noonan and 3M syndrome. 22 novel genes with potential impact on growth have been identified and are currently under further investigation.

Volume 39

43rd Meeting of the British Society for Paediatric Endocrinology and Diabetes

British Society for Paediatric Endocrinology and Diabetes 

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