Abstract
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. 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. 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. 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. 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.
Highlights
Short stature is one of the most common reasons for referral to paediatric endocrinologists
Depending on the genetic defect, associated clinical and dysmorphic features may be present including midfacial hypoplasia and frontal bossing (GHR, STAT5B) (4, 11), immune deficiency (STAT5B) (4), pubertal delay (IGFALS, STAT5B, GHR) (4, 11, 12), decreased bone mineral density (PAPPA2) (7), developmental delay, microcephaly and in-utero growth retardation (IGF1, IGF1R) (1). 3M, Silver–Russell (SRS) and Noonan (NS) syndromes have phenotypes that can overlap with growth hormone (GH) insensitivity (GHI) (10, 13, 14). 3M syndrome (OMIM 273750) results in pre- and post-natal growth restriction, prominent heels, facial dysmorphism and distinct radiological features (15)
candidate gene sequencing (CGS) identified likely causative variants in 35 GHI patients (28 probands) and 3 IGF-1 insensitivity patients, all probands (Table 1). These included variants in GHR (n = 27 patients), IGFALS (n = 3 patients), obscurin-like 1 (OBSL1) (n = 6 patients), cullin 7 (CUL7) (n = 1 patients) and IGF1R (n = 1 patient) (Figs 1A and 2). 30 of 38 (79%) children diagnosed by CGS had consanguineous parents
Summary
Short stature is one of the most common reasons for referral to paediatric endocrinologists. Patients with defects in growth hormone (GH) action or GH insensitivity (GHI) frequently present with severe phenotypes 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. 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. WES revealed 11 patients with genetic variants in genes known to cause short stature. 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
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