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, Lucy; Chatterjee, Sumana; Ramadan, Dina; Davies, Kate; Savage, Martin O.; Metherell, Louise A.; Storr, Helen L

doi:10.1530/eje-17-0453

Cited by 35 publications

(34 citation statements)

References 38 publications

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“…Homozygous GHR mutations are the commonest cause of 'classical' GHI and are associated with a wide range of clinical and biochemical phenotypes (33). More recently, it has been noted that several other short stature disorders such as 3M, Noonan Syndrome (NS) and Silver-Russell Syndrome (SRS) overlap with GHI (2,34,35,36,37).…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 70 different GHR gene mutations have been reported in more than 300 patients (1,2). A recent UK study (37) reporting the genetic diagnoses obtained from candidate gene and whole exome sequencing (WES) in a selected group of 107 patients with GHI showed that the GHR 6Ψ mutation contributed to 25% (8/32) of GHR mutations and 16% (8/51) of all genetic diagnoses.…”

Section: Discussionmentioning

confidence: 99%

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GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Chatterjee

Cottrell

Rose

et al. 2020

Endocrine Connections

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Objectives The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this. Methods 6Ψ-GHR and WT-GHR mRNA transcripts of four 6Ψ patients (height SDS −4.2 to −3.1) and one control fibroblast were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing. Results RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not in the control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29–71:1 for patients 1–4 and correlated negatively with height SDS (R = −0.85; P < 0.001). Eight deleterious variants in six genes were detected, but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients. Conclusion Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT-GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Chatterjee

Cottrell

Rose

et al. 2020

Endocrine Connections

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“…GHI-IGF-1 axis defects overlap with several other congenital syndromes such as Noonan syndrome (MIM: 163950), 3M syndrome (MIM: 273750) and Silver–Russell syndrome (SRS, (MIM: 180860)) ( 8 ). We previously reported two patients who presented with ‘classical’ GHI who were diagnosed with SRS secondary to 11p15LOM and upd( 7 )mat ( 8 , 9 ). SRS is a clinical diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity

Cottrell

Cabrera

Ishida

et al. 2020

European Journal of Endocrinology

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Objective: Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1). Design and Methods: Array Comparative Genomic Hybridisation was performed with ~60,000 probe oligonucleotide array in GHI (n=53) and IGF-1 insensitivity (n=10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions. Results: Both cohorts were enriched for class 3-5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n=2), 12q14 (n=1) deletions and Xp22 (n=1), Xq26 (n=1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts. Conclusions: Our cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.

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“…Short stature can be caused by many factors, such as endocrine, genetic, environmental, nutritional, psychological, metabolic, and clinical factors. The GH/insulin-like growth factor-1 (IGF-1) axis plays an important role during critical periods of child growth and development [2,3].…”

Section: Introductionmentioning

confidence: 99%

Association between Haemoglobin and Growth Hormone peak in Chinese Children and Adolescents with Short Stature: A Cross-Sectional Study

Zhang

Ban

Zhang

et al. 2020

Preprint

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Background: This research aimed to investigate the relationship between haemoglobin (Hb) and growth hormone (GH) peak in children and adolescents with short stature.Methods: This cross-sectional study included a total of 787 children and adolescents with short stature. Anthropometric and biochemical indicators were measured at baseline. All patients underwent GH provocation tests with L-dopa and insulin to assess GH peak levels.Results: The univariate analysis results showed that Hb was positively associated with GH peak (β 0.07, P=0.001). Furthermore, a non-linear relationship was detected between Hb and GH peak in multivariate piecewise linear regression analysis, and the breakpoint was 123 g/L. GH peak increased with Hb elevation when the Hb level was greater than 123 g/L (β 0.08, 95% CI 0.01, 0.14; P=0.0207). However, when the Hb level was lower than 123 g/L, there was no significant relationship between Hb and GH peak (β -0.12, 95% CI -0.30, -0.06; P = 0.1867).Conclusion: In children and adolescents with short stature, we found a non-linear association between Hb and GH peak. These findings suggest that clinicians should pay more attention to Hb levels in patients with short stature.

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Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity

Cited by 35 publications

References 38 publications

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity

Association between Haemoglobin and Growth Hormone peak in Chinese Children and Adolescents with Short Stature: A Cross-Sectional Study

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