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

Cottrell, Emily; Cabrera, Claudia; Ishida, Miho; Chatterjee, Sumana; Greening, James; Wright, Neil; Bossowski, Artur; Dunkel, Leo; Deeb, Asma; Basiri, Iman Al; Rose, Stephen; Mason, Avril; Bint, Susan; Ahn, Joo Wook; Hwa, Vivian; Metherell, Louise; Moore, Gudrun E.; Storr, Helen L

doi:10.1530/eje-20-0474

Cited by 5 publications

(8 citation statements)

References 49 publications

(78 reference statements)

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“…The first cases of microscopic deletions in 1q21 have been published by Spengler et al [ 8 ] (Table 1 a, Fig. 1 a), and meanwhile four further cases with such alterations have been identified by molecular karyotyping in suspected SRS patients [ 9 , 10 ]. Furthermore, genomic alterations of the PLAG1 gene in 8q12.1 have recently been identified in patients with an SRS phenotype, including both SNVs [ 4 – 6 , 11 ] and CNVs [ 12 , 13 ] (Table 1 b, Fig.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, in several public databases (DECIPHER, ClinVar), further cases with deletions affecting these regions are documented, but none of them exhibited alterations of similar size. Nearly all patients have been referred for molecular karyotyping due to clinical features of SRS, but only the NHS criteria are shown here Symptoms Our case [ 9 ] [ 8 ] SR9116 [ 8 ] SR5695 [ 10 ] patient 1a [ 10 ] patient 1b [ 10 ] patient 2 Frequency a Information on 1q21.1q21.2 cases Variant Affected 1q21.1q21.2 region (GRCh37) 145,895,747–147,897,962 145,261,451–148,343,412 145,770,626–147,831,171 145,932,455–147,831,171 146,564,742–147,735,011 146,641,600–147,735,011 145,987,155–147,735,011 Size of the deletion 2 Mb 3 Mb 2 Mb 1.9 Mb 1.17 Mb 1.09 Mb 1.74 Mb Parental origin de novo de novo maternal not maternal maternal maternal de novo NH-CSS criteria SGA/IUGR 0 0 1 1 NA NA NA 50.0% (2/4) Height at 2 years (< -2 SD) 0 1 …”

Section: Introductionmentioning

confidence: 99%

“…Our patient (red bar 1) carries a 2 Mb deletion in 1q21.1q21.2 (arr(GRCh37) 1q21.1q21.2(145,895,747_147,897,962) × 1). To compare the extent of our patient’s deletion to patients from the literature (Azzi et al 4 , Spengler et al[ 8 ], Cottrell et al [ 10 ] only the SRS candidate genes discussed by [ 10 ] are shown. The green bar displays the well known 1q12.2 microdeletion syndrome .…”

Section: Introductionmentioning

confidence: 99%

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Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

et al. 2022

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Background Silver-Russell syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction, relative macrocephaly at birth, body asymmetry and typical facial features. Clinical and molecular heterogeneity is described in SRS. Common causes are loss of methylation of the imprinting center 1 in 11p15 and maternal uniparental disomy of chromosome 7. Other genetic alterations include disturbances of imprinted regions in 14q32, 7q32 and 11p15 as well as submicroscopic deletions and duplications. Single nucleotide variants in genes like IGF2, HMGA2, PLAG1, CDKN1C have also been identified in patients with SRS phenotypes. However, routine molecular diagnostics usually focus on 11p15 and chromosome 7, while less frequent causes are not systematically addressed. Results Here we report two patients with SRS features in which molecular karyotyping revealed microdeletions in 1q21 and 8q12.1 respectively. In a 3.5-year-old girl with postnatal growth restriction, feeding difficulties, relative macrocephaly and distinct SRS features a 2 Mb deletion in 1q21.1q21.2 was identified. Our second case is a 1.5-year-old boy with intrauterine and postnatal growth restriction, feeding difficulties and distinct facial features with a 77 kb deletion in 8q12.1 affecting PLAG1 as the only protein-encoding gene with known function. Conclusions The 1q21 region has not yet been assigned as an SRS region, although six patients with the same deletion and SRS features including relative macrocephaly have been described before. This new case adds to the evidence that distal 1q21 should be annotated as an SRS candidate region. The PLAGL1 alteration is the smallest deletion in 8q12.1 ever reported in a patient with SRS phenotype and it finally confirms that PLAG1 is the SRS causing gene in 8q12.1. To increase the diagnostic yield in patients with suspected SRS, we recommend both molecular karyotyping and next generation sequencing-based approaches.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

et al. 2022

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“…The other subjects had a 5q12 deletion (Class 3), Xq26 deletion (Class 4), duplication of chromosome 10, a combination of 7q21 (Class 3) and 7q31 (Class 4) deletions, combined (Class 3) 7q21 and Xp22 duplication, 7q36 duplication (Class 3) and combined 3p22 deletion (Class 3), and combined 15q13 (Class 4) duplication and 3p22 (Class 3) deletion. Nine of these CNVs are described in our recent publication ( 46 ).…”

Section: Resultsmentioning

confidence: 99%

Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes

Andrews

Maharaj

Cottrell

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context and objective Growth hormone insensitivity (GHI) in children is characterized by short stature, functional IGF-I deficiency and normal or elevated serum GH concentrations. The clinical and genetic etiology of GHI is expanding. We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects. Design and methods Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing (CGS), whole exome sequencing (WES), array comparative genomic hybridization (aCGH) and a targeted whole genome short stature gene panel. Results Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n=40, IGFALS n=4, IGFIR n=1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n=10) (OBSL1 n=7, CUL7 n=2 and CCDC8 n=1), Noonan syndrome (n=4) (PTPN11 n=2, SOS1 n=1 and SOS2 n=1), Silver-Russell syndrome (n=2) (Loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n=10) and disorders not previously associated with GHI (n=9) (Barth syndrome, Autoimmune lymphoproliferative syndrome, Microcephalic osteodysplastic primordial dwarfism Type II, Achondroplasia, Glycogen storage disease Type IXb, Lysinuric protein intolerance, Multiminicore Disease, MACS syndrome and Bloom syndrome). Conclusion We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.

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“…Growth hormone can also promote growth and development by forming a ternary complex with IGF-1 and IGFBP-3. 20 Indeed, a study on 50 patients with growth hormone deficiency showed that IGF-I and IGFBP-3 were highly sensitive and specific for diagnosing GHD. 21 In our study, IGF-1 and IGFBP-3 levels were higher in the high-dose group, indicating that exogenous rhGH supplementation can promote physical development through elevating these two hormones.…”

Section: Discussionmentioning

confidence: 99%

Effects of high-dose recombinant human growth hormone treatment on IGF-1 and IGFBP-3 levels in idiopathic dwarfism patients

Wu¹,

Lin²,

Gao³

et al. 2022

Pak J Med Sci

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Objective: To investigate the effects of high-dose recombinant human growth hormone(rhGH) treatment on insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in patients with idiopathic dwarfism. Methods: This study retrospectively investigated records of idiopathic dwarfism patients treated at Anhui Children’s Hospital or the Affiliated Hospital of Xuzhou Medical University between May 2019 and October 2020. The study identified 76 patients, which were divided based on rhGH treatment dosage into high- and low-dose groups. Results: The high-dose group showed a total efficacy of 95.3%, which was significantly higher than the 79.41% observed in the low-dose group (P<0.05). Moreover, height, weight, IGF-1 levels, and IGFBP-3 levels were all significantly elevated in the high-dose group compared to the low-dose group (P<0.05). No significant difference in adverse reaction incidence was observed between high- (9.5%) and low-dose (8.8%) groups (P>0.05). Conclusions: Higher doses of rhGH can provide improved curative effects in patients with idiopathic short stature, likely via elevated levels of IGF-1 and IGFBP-3. doi: https://doi.org/10.12669/pjms.38.4.5502 How to cite this:Wu B, Lin H, Gao J, Sun J, Zhao M. Effects of high-dose recombinant human growth hormone treatment on IGF-1 and IGFBP-3 levels in idiopathic dwarfism patients. Pak J Med Sci. 2022;38(4):---------. doi: https://doi.org/10.12669/pjms.38.4.5502 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Cited by 5 publications

References 49 publications

Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes

Effects of high-dose recombinant human growth hormone treatment on IGF-1 and IGFBP-3 levels in idiopathic dwarfism patients

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