Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity
Shapiro, L, Chatterjee, S, Ramadan, DG, Davies, KM, Savage, MO, Metherell, LA and Storr, HL (2017). Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity. European Journal of Endocrinology. 177 (6), pp. 485-501. https://doi.org/10.1530/EJE-17-0453
|Authors||Shapiro, L, Chatterjee, S, Ramadan, DG, Davies, KM, Savage, MO, Metherell, LA and Storr, HL|
Background GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown.
Objective To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect.
Methods We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS.
Results A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver–Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect.
Conclusions Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.
|Journal||European Journal of Endocrinology|
|Journal citation||177 (6), pp. 485-501|
|Digital Object Identifier (DOI)||https://doi.org/10.1530/EJE-17-0453|
|Online||04 Sep 2017|
|Publication process dates|
|Accepted||04 Sep 2017|
|Deposited||16 Sep 2020|
|Accepted author manuscript|
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Disclaimer: this is not the definitive version of record of this article. This manuscript has been accepted for publication in European Journal of Endocrinology, but the version presented here has not yet been copy-edited, formatted or proofed. The definitive version is now freely available at https://doi.org/10.1530/EJE-17-0453, 2017.
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