Introduction

Biomedical Reports

2049-9434 2049-9442

D.A. Spandidos

BR-24-6-02151

10.3892/br.2026.2151

Articles

Roles of insulin-like growth factor 1 receptor in growth regulation in 15q26 deletion and duplication syndrome

Kexin

1 Xu

Xin

2 Liu

3 Zhang

4 Lu

Yulan

5 Dong

Xinran

3 Wang

Laishuan

4 Cheng

Guoqiang

4 Wang

Jin

4 Lu

Wei

1 Wu

Bingbing

3 Wang

Huijun

3 Luo

Feihong

1 Zhou

Wenhao

5 Yang

Lin

1Department of Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai 201102, P.R. China 2Division of Neonatology, Children's Hospital of Fudan University (Xiamen Branch), Xiamen Children's Hospital, Xiamen, Fujian 361006, P.R. China 3Center for Molecular Medicine of Children's Hospital of Fudan University, Shanghai 201102, P.R. China 4Division of Neonatology, Children's Hospital of Fudan University, Shanghai 201102, P.R. China 5Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, P.R. China

Correspondence to: Dr Lin Yang, Department of Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, P.R. China yanglin_fudan@163.com

062026

28042026

24 6

23 05 2025 13 02 2026

2026

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The 15q26 deletion and duplication syndromes are rare chromosome diseases with growth deviation and structural anomalies such as facial abnormality, cardiac malformation and hand/foot/skeleton malformations. Insulin-like growth factor 1 receptor (IGF1R), located on chromosome 15q26, is key for pre- and postnatal growth. The present study aimed to determine whether IGF1R serves as a key factor in growth regulation in 15q26 deletion and duplication syndromes. Patients with 15q26 deletions and duplications enrolled in the China Neonatal Genomes Project (CNGP) were recruited. A systematic review of 15q26 deletion and duplication cases was performed, followed by meta-analysis to evaluate the roles of IGF1R and three other genes [myocyte enhancer factor 2A (MEF2A), leucine-rich repeat kinase 1 (LRRK1) and nuclear receptor subfamily 2 group F member 2] involved in growth regulation. A total of 10 eligible patients from the CNGP, including seven with deletions and three with duplications, were identified. The literature search and screening yielded 78 patients with 15q26 deletions and 10 with 15q26 duplications. Clinical features observed in >70% of the patients in the deletion group were facial abnormalities, developmental delay, short stature and hand/foot/skeleton malformations, whereas the duplication group exhibited facial abnormality, hand/foot/skeleton malformation and speech development delay. In 15q26 deletion, three candidate genes were associated with an increased risk of short stature: IGF1R [odds ratio (OR): 8.43; 95% confidence interval (CI): 2.22-32.00], LRRK1 (OR: 100.00; 95% CI: 11.86-843.23) and MEF2A (OR: 32.21; 95% CI: 3.81-272.47). In 15q26 duplication, none of the candidate genes significantly affected tall stature. Using meta-analysis, the present study revealed that IGF1R is not the only key gene responsible for growth abnormalities in 15q26 deletion and duplication syndromes.

IGF1R gene short stature tall stature 15q26 deletion syndrome 15q26 duplication syndrome

Funding: No funding was received.

Introduction

Abnormalities in the distal long arm of chromosome 15 are associated with various clinical manifestations. Specifically, 15q26 deletion is associated with intrauterine growth restriction (IUGR), small for gestational age (SGA), microcephaly, developmental delay, skeletal abnormality and dysmorphic facial features (1). Distal duplication of 15q is involved in overgrowth syndrome and other congenital malformations, including craniosynostosis, cardiac and renal malformation, genital and limb abnormality (2). Chromosomal alterations on 15q26 may occur as a de novo event leading to deletion/duplication or as a consequence of ring chromosome formation and unbalanced translocation (2,3).

Insulin-like growth factor 1 receptor (IGF1R), located on chromosome 15q26.3, is dosage-sensitive (4). Biological functions of IGF-1, including its roles in intrauterine development, postnatal growth and metabolism, are primarily mediated by IGF1R (5). Associations between poor growth and overgrowth in 15q26 deletion and duplication syndromes, respectively, are associated with the dysregulation of IGF1R expression. To the best of our knowledge, however, research on this has been limited to case reports or reviews (1,3), yielding inconsistent results. Therefore, comprehensive evaluation using a large sample size is necessary to clarify this association.

The present study involved patients with 15q26 deletion/duplication from the Chinese Neonatal Genomes Project (CNGP) (6) enrolled at Children's Hospital of Fudan University, Shanghai, China. The clinical symptoms of patients with 15q26 deletions and duplications were systematically reviewed through a comprehensive literature review. Furthermore, a meta-analysis was performed to assess the effects of IGF1R, nuclear receptor subfamily 2 group F member 2 (NR2F2), myocyte enhancer factor 2A (MEF2A) (3) and leucine-rich repeat kinase 1 (LRRK1) (7) on the poor growth and overgrowth of patients with 15q26 deletion/duplication. The present study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (8). Identification of key genes associated with growth in 15q26 deletion/duplication may provide insights into the pathological mechanisms underlying cytogenetic defects, facilitating the development of effective management strategies.

Patients and methods <sec> <title>Study population

Ethics approval was provided by the Ethics Committee of the Children's Hospital of Fudan University, Shanghai, China (approval nos. 2021-375 and 2025-40). The parents of participants provided informed written consent for genetic testing. The inclusion criteria were as follows: i) Patients admitted to the neonatal intensive care unit of the Children's Hospital of Fudan University between August 2016 and July 2022 as part of CNGP; ii) patients with deletion or duplication copy number variations (CNVs) on chromosome 15q26 and iii) cases with CNVs >1 Mb.

The exclusion criteria were as follows: i) Patients with CNVs other than 15q26 deletion or duplication; ii) patients with single nucleotide variants (SNVs); and iii) patients with incomplete clinical information.

A total of 10 newborns, including four females and six males were enrolled in the study. The median last follow-up age was 6.4 years (range, 3.0-9.7 years). Clinical data were collected, including discharge diagnosis, physical examination, hospitalization history during the neonatal period and health examination record during follow-up. The assessment of body size at birth and follow-up was according to growth standard curves and standardized growth charts for Chinese newborns and children (9,10). Most of the available data were confined to the neonatal period. Therefore, the present study used a composite outcome that encompassed either IUGR/SGA at birth or short stature in childhood as an indicator of a growth disorder. Similarly, overgrowth was defined by a composite outcome comprising either large for gestational age (LGA) or tall stature.

Whole exome sequencing and CNV analysis based on sequencing data

At enrollment, 1 ml blood was drawn from each patient and anticoagulated with EDTA. Genomic DNA was extracted using the QIAamp DNA kit (Qiagen GmbH; cat. no. 51185). The concentration was measured using a NanoDrop 2000 ultraviolet spectrophotometer (Thermo Fisher Scientific, Inc.). Agilent SureSelect XT Human All Exon V5 kit (Agilent Technologies, Inc.; cat. no. 5190-6209) was used for library capture. The loading concentration of the final library was 10-14 pM. Paired-end sequencing (125/150 bp) was performed using the Illumina, Inc. HiSeq 2000/2500 platform. The average coverage for the yielded data was 124.05X, and the average fraction of target covered with at least 10X and 20X were 99.11% and 97.17%, respectively. Low-quality reads (reads containing >10% unknown bases or >50% bases with a sequencing quality <5) were removed from the raw fastq data to generate clean reads. Clean reads were aligned to the reference human genome (University of California, Santa Cruz (UCSC hg19) using the Burrows-Wheeler Aligner (BWA; v.0.5.9-r16, sourceforge.net/projects/bio-bwa/files/), sorted by SAMtools (v.1.8, https://sourceforge.net/projects/samtools/files/samtools/), and deduplicated using Picard (v.2.20.1, https://github.com/broadinstitute/picard/releases/tag/2.20.1). CNGP clinical sequencing pipeline was as previously described (11).

CNVs were screened via second-generation sequencing as follows (11): i) CNV data of duplication fragments >500 kb and deletion fragments >200 kb were selected; ii) false positive results were excluded; iii) CNVs reported as a normal population in the International Genome CNV Polymorphism database (Database of Genomic Variants, dgv.tcag.ca/); ≥80% overlap of fragments and the same type of duplication or deletion were excluded; and iv) CNVs that did not contain genes in the region were excluded.

The molecular diagnostic laboratory at Children's Hospital of Fudan University implemented a well-established CNV analysis pipeline using exome sequencing (ES), called PICNIC, encompassing CNV detection, annotation and filtration (11,12). The accuracy of the ES call CNV performance >1 Mb has been demonstrated in identifying pathogenic/likely pathogenic (P/LP) CNVs (12-14). PICNIC identifies candidate CNVs (predicted P/LP or variants of uncertain significance CNVs) in each case for manual review. Breakpoints and sizes were determined according to the predefined exome. PICNIC default settings favor sensitivity to prevent the loss of positive results and false-positive results were excluded through manual review.

Systematic review

The present study aimed to assess the impact of IGF1R gene along with NR2F2, LRRK1 and MEF2A genes on poor growth and overgrowth in patients with 15q26 deletion/duplication. A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist (8).

Literature search was performed in the PubMed database (pubmed.ncbi.nlm.nih.gov) using the search term ((15q26[Title/Abstract]) OR (15q terminal[Title/Abstract]))AND (English[Filter]) from February 1983 to August 2025. The individual-level data of the patients involving 15q26 deletion/duplication and the genotype and primary phenotypes of both deletion and duplication cases were collected. EndNote 20.4 (endnote.com/) was used for the reference management. The inclusion criteria were as follows: i) Case reports or reviews; ii) genetic testing results indicating a 15q26 deletion or duplication; iii) cases with detailed phenotypic and genotypic data; iv) Only cases of 15q26 syndrome published in the English language were included. The exclusion criteria were as follows: i) Studies without detailed information on phenotype and genotype; ii) unrelated studies, such as those focusing on SNVs or cancer research; iii) tetraploidy on 15q26 chromosome; and iv) patients with CNVs other than 15q26 deletion/duplication.

A total of two investigators reviewed the titles and abstracts of all publications identified in the literature search. The data were extracted and assigned to the following domains: i) Literature characteristics (author and year); ii) patient demographic information (age and sex); iii) clinical manifestations (IUGR, SGA, LGA, cardiac malformation, tall stature, growth retardation/failure to thrive/short stature, developmental delay, microcephaly, macrocephaly, facial abnormality, speech development delay and hand/foot/skeleton malformations); and iv) genotypes (chromosome band, location, deletion/duplication, CNV size, ring chromosome 15). If the gene was not mentioned and the chromosomal location was not provided, the involvement of the gene could not be confirmed. Individuals with partial genetic information were retained for clinical profiling. However, genes that could not be confirmed were annotated as not available and were not included in the final statistical analysis. If main clinical information was present, cases passed the quality assessment.

Statistical analysis

Clinical manifestations were summarized as frequency counts and compared using the Pearson χ² or the Fisher exact test. Microcephaly was defined as an occipitofrontal head circumference (OFC) below the third centile or >2 SD below the mean for sex, age and ethnicity (15). Macrocephaly was defined as an OFC >2 SD or 0.5 cm above the 97th percentile (16). SGA and LGA were defined as a birth weight and/or length <10th percentile or >90th percentile, or with a Z-score less than -2 or greater than +2 for gestational age and sex, respectively (9,17,18). Short and tall stature were defined as a height with a Z-score <-2 or greater than +2, or below the 3rd or above the 97th percentile for age and sex (10,19). The mechanism by which the target genes contributed to short/tall stature in patients with 15q26 syndrome was assessed using Review Manager 5.4 (Nordic Cochrane Centre). IUGR, SGA, short stature, growth retardation and failure to thrive were regarded as short stature-positive events in 15q26 deletion, whereas LGA and tall stature were regarded as tall stature-positive events in 15q26 duplication. Mantel-Haenszel (M-H) test was used for stratified analysis. All outcomes are reported as odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous data. I² statistic was used to measure the heterogeneity of studies. A random-effects model was used for meta-analyses. SPSS software version 26 (IBM Corp) was used for the data analysis. P<0.05 was considered to indicate a statistically significant difference.

Results <sec> <title>Clinical features and genetic results of patients enrolled in CNGP

A total of 10 eligible patients from CNGP were included (Table I). There were three patients in the duplication and seven patients in the deletion group. The duplication group consisted of one female and two male patients. One patient was diagnosed with SGA (Patient 1) and one with LGA (Patient 2). The deletion group consisted of four males and three females. Among them, six patients (patient 4, 5, 7, 8, 9, 10) were diagnosed with short stature. Patient 6 was born with SGA and was not of sufficient age to undergo follow-up measurement. A total of four patients (patients 4, 7, 8 and 10) were diagnosed with developmental delay and two patients (patients 4 and 5) had hip abnormalities. Patient 7 was diagnosed with congenital heart disease and cryptorchidism.

In the duplication group (Table I), there were two duplications at 15q26.1 and 15q26.3 in patient 1. Among the candidate genes, NR2F2 was normal, whereas the others were duplicated in Patient 1. Patient 2 had a 10.95 Mb duplication at 15q26.1-q26.3, involving all four genes. Patient 3 had a duplication at 15q26.1, but the candidate genes had a normal karyotype. In the deletion group, six patients (patients 5-9) exhibited a deletion at 15q26.3 and one patient (patient 10) exhibited a deletion at 15q26.1. IGF1R and MEF2A were involved in the CNVs of four patients (patients 4-7). The sizes of deleted regions varied from 1.2 to 4.2 Mb. LRRK1 was only normal in patient 10. Notably, NR2F2 was not deleted in any patient of the deletion group.

Literature review and study characteristics

A total of 326 studies was retrieved from PubMed (Fig. 1). Of these, 176 articles were excluded after title selection and 37 were excluded after abstract selection. In total, 113 studies were eligible for detailed review. Clinical manifestations and genetic findings of cases were collected; 44 cases were excluded as they involved other CNVs, and 21 were excluded because they lacked detailed clinical or genetic information. Finally, 88 cases from 64 studies were subjected to meta-analysis (Tables II and SI) (1-4,7,20-78). A total of 78 patients had deletions and 10 had duplications. The length of deletions ranged from 2 kb to 13.3 Mb, whereas that of duplications ranged from 290 kb to 4.71 Mb.

Phenotype characteristics

A total of 88 cases were collected (Table I and Table SI). Excluded studies/patients (mostly cases with chromosomal translocations) are presented in Table SII.

In the deletion group (Table I), the most frequently observed clinical features were facial abnormality (65/77, 84.4%), developmental delay (49/61, 80.3%), growth retardation/short stature (58/71, 81.7%), hand/foot/skeleton malformation (55/76,72.4%), SGA (43/64, 67.2%), speech developmental delay (31/50, 62.0%) and microcephaly (39/66, 59.1%). Cardiac malformations were observed in 38.7% of cases (29/75).

In the duplication group (Table I), the most frequently observed clinical features were facial abnormality (10/10, 100.0%), hand/foot/skeletal malformation (6/7, 85.7%), speech development delay (5/6, 83.3%) and tall stature (4/7, 57.1%). Macrocephaly was observed in 28.6% (2/7), LGA in 25.0% (2/8), developmental delay in 16.7% (1/6), SGA in 12.5% (1/8) and cardiac malformation in 12.5% (1/8) of cases.

Significant differences in age were observed between the deletion and duplication groups. The literature review also revealed significant differences in SGA/LGA, growth retardation, short/tall stature, developmental delay and microcephaly between the deletion and duplication groups. However, no significant differences in cardiac malformation, macrocephaly, facial abnormality, speech development delay and hand/foot/skeleton malformation were observed between the two groups.

Effects of candidate genes on patient growth

Chromosome locations of deletion and duplication cases with specific positions are presented in Fig. 2. The present study assessed the effects of candidate genes on the growth of patients with 15q26 duplication/deletion syndrome using M-H test (Figs. 3 and 4). In 15q26 deletion, three candidate genes were associated with an increased risk of short stature: IGF1R (OR: 8.43; 95% CI: 2.22-32.00), LRRK1 (OR: 100.00; 95% CI: 11.86-843.23) and MEF2A (OR: 32.21; 95% CI: 3.81-272.47). LRRK, not IGF1R, was more likely to result in short stature. NR2F2 (OR: 3.48; 95% CI: 0.69-17.64) was not significantly associated with short stature. In 15q26 duplication, all candidate genes, IGF1R (OR: 2.67; 95% CI: 0.28-25.64), LRRK1 (OR: 11.00; 95% CI: 0.46-263.53), MEF2A (OR: 10.50; 95% CI: 0.67-165.11) and NR2F2 (OR: 12.14; 95% CI: 0.46-323.23) were not significantly associated with tall stature. In addition, there were 18 ring chromosome 15 cases, including 17 in the deletion and one in the duplication group (Table SI).

Discussion

The 15q26 deletion/duplication syndrome is a rare genetic disease that causes syndromic manifestations such as facial abnormality, growth problems, cardiac and hand/foot/skeleton malformation and developmental delays. A total of 58 cases of pure 15q26 deletions have been reported up to September 2021(3) and >70 patients with chromosome 15q terminal duplications were reported in 2017(28). The present study collected cases with 15q26 deletions or duplications to delineate the role of implicated genes within this region and characterize the spectrum of associated clinical features. The analysis of 98 cases (88 cases in literature and 10 cases from CNGP) in the present study revealed that IGF1R may not be the only gene responsible for the phenotype of chromosome 15q26 deletion/duplication syndrome. The present study performed meta-analysis to explore the 15q26 region for key genes associated with growth regulation of 15q26 deletion/duplication syndrome.

Previous reports (1,21,67,73) mostly attribute growth abnormality to IGF1R gene in 15q26 deletion/duplication syndrome. IGF1R gene, which is mapped to chromosome 15q26.3, is a member of the insulin receptor family. It functions by activating the downstream mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B signaling pathways (79). Holzenberger et al (80) introduced a neomycin resistance cassette into intron 2 of IGF-1R. This insertion interfered with the processing of the primary transcript, resulting 12% fewer IGF-binding sites at the cell surface in heterozygous mice and 41% fewer in homozygous mice. Hetero- and homozygous offspring grew more slowly than wild-type littermates. Functional deficit of IGF1R gene affects the postnatal growth (80). A previous report showed that a patient with 15q-trisomy had postnatal overgrowth and three copies of IGF1R, whereas a fetus with 15q-monosomy showed IUGR with one copy of IGF1R gene; these were all derived from paternal balanced translocation (81). IGF1R gene defects cause intrauterine and postnatal growth failure, microcephaly and developmental delays in autosomal dominant (AD) and autosomal recessive (AR) inheritance models (82-84). Patients with AR inheritance are more severely affected than those with AD inheritance by IGF1R defect with developmental and speech delays (85). IGF1R is key for normal embryonic and postnatal growth (86), especially skeletal growth, brain development and carbohydrate metabolism (1). Patients with IGF1R mutations exhibit biochemical features of IGF-I resistance, with high circulating concentrations of IGF-I and growth hormone (86). Veenma et al (45,46) considered that in addition to short stature, most clinical features of 15q26 deletion syndrome are similar to those caused by single mutations in IGF1R. Walenkamp et al (87) developed a clinical scoring system for the diagnosis of IGF1R defect that was tested in single cohort (88). Since the present cases did not receive IGF level testing as a routine during their hospitalization in the neonatal period, independent sample tests could not be conducted. The clinical score should be conducted in future longitudinal studies.

The present and previous studies reported short and tall stature cases without IGF1R deletions or duplication (7,54). A total of three of the present patients (patients 8-10) had SGA/short stature without IGF1R deletion. The deletions in patients 8 and 9 overlapped those reported by Bellucco et al (89) and Szabo et al (90). Conversely, certain duplication cases may not demonstrate an LGA phenotype. Patients may exhibit IUGR (2). In addition to the IGF1R gene, haploinsufficiency of the 15q26 genomic region distal to IGF1R gene may be related to growth disturbance without loss of the IGF1R gene. MEF2A, NR2F2 and LRRK1 were considered candidate genes that contributed to 15q26 deletion/duplication syndrome (3,6).

LRRK1 gene is a strong candidate gene, as evidenced by prior literature implicating its contribution to growth phenotype in the 15q26 deletion/duplication syndrome (6,75). LRRK1 encodes a multi-domain protein that is a leucine-rich repeat kinase and a GDP/GTP binding protein. The encoded protein is hypothesized to play a role in the regulation of bone mass. In Online Mendelian Inheritance in Man database (91), mutations in the LRRK1 gene are associated with osteosclerotic metaphyseal dysplasia, an AR disorder presenting with skeletal abnormality and notably short stature. The protein encoded by MEF2A gene is a DNA-binding transcription factor that activates numerous muscle-specific and growth factor- and stress-induced genes, such as PIK3CG and MMP9 genes (92,93). MEF2A gene mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. NR2F2 encodes a ligand-activated transcription factor. NR2F2 gene defects cause a variable syndrome of congenital anomalies, commonly associated with heart defect, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia and genital anomalies (94). In the Genecards database (genecards.org), LRRK1, MEF2A and NR2F2 genes are associated with body height. The deletions of these genes on 15q26 region may be involved in the occurrence of short stature, along with abnormalities in cardiovascular, skeletal and nervous systems. LRRK1 and MEF2A gene demonstrated higher OR than IGF1R gene. However, these results exhibited relatively wide CIs, indicating a higher degree of uncertainty. The present sample size was relatively limited, particularly for cases with duplications. To investigate the impact of genetic alterations within the 15q26 region on phenotypic outcomes, the present study excluded cases with additional chromosomal abnormalities other than this region, including those involving chromosomal translocations and cases with breakpoints proximal to 15q26 region, which lead to the censored data of numerous candidate samples. The majority of individuals affected by 15q26 alterations presented with physical developmental disorder. The present study aimed to delineate the underlying gene-phenotype associations through calculating OR. However, CNV-associated phenotypes are not only driven solely by single genes, but also typically involve multiple contiguous genes. When genes are located in close proximity and are concurrently deleted or duplicated, the combined effects may confound analyses (95-98). As a result, the CI in the present study may be relatively wide.

The present study focused on analyzing the association between deletion/duplication of genes and growth phenotypes, specifically the impact of sequence alterations, and therefore excluded cases with aberrations in other chromosomal segments. The present literature review included 18 cases with ring chromosomes. Previous studies (28,68,70) have suggested that patients with ring chromosome 15 present with similar clinical features to those with pure 15q26 deletion, and short statures observed in r(15) patients are likely related to reduced dosage of the IGF1R gene. In our study, we aimed to explore the effects of IGF1R gene on growth phenotype. Therefore, we considered r(15) as a type of 15q26 deletions/duplications and included cases with r(15) according with our inclusion criteria. However, due to the limited number of r(15) cases, the present study did not perform a separate analysis of the impact of the ring structure on short stature. Another potential factor is that a promoter region change affects gene expression: Different breakpoints may lead to the juxtaposition of IGF1R near an active promoter or to alteration of normal regulatory sequences of the gene. Also, embryonic development and growth may not only be influenced by genetic factors, but also affected by environmental factors, including maternal factors and nutrition.

Here, duplication cases were relatively rare compared with deletion cases. Although none of the four genes showed a significant contribution to tall stature in the duplication group, a consistent trend of positive effects on overgrowth was observed. However, the insufficient sample size led to a decrease in the statistical power and findings should be interpreted with caution. During data extraction and screening, chromosome abnormalities other than 15q26 were excluded, including cases that had deletions or duplications in the proximal region of 15q26 because other chromosome anomalies may lead to more complex phenotypes in patients. Numerous cases of 15q duplication involved large-scale duplications, which exceeded 15q terminal (15q26) region and were excluded from the present study.

The present retrospective study reported 10 cases of 15q26 deletion and duplication syndrome in CNGP, including three patients with 15q26 duplication and seven with 15q26 deletion. Additional phenotypes associated with the IGF1R were reported, such as microcephaly and hypotonia. The clinical features were similar to those reported in the literature (31,35). Microcephaly was more prevalent in 15q26 deletion cases, while macrocephaly was more prevalent in 15q26 duplication cases. Congenital heart disease was present in both deletion and duplication cases. A high prevalence of congenital heart defects has been reported in cases of IGF1R gene defects (28). A previous study in mice have suggested conditional deletion of IGF-1R and the insulin receptor genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia (99). However, alterations in the NR2F2 and MEF2A gene may explain heart defects found in the 15q26 syndrome as well. The pathogenic mechanisms underlying congenital heart defects of the 15q26 syndrome remain to be fully elucidated. A total of two male patients with CNGP were diagnosed with cryptorchidism, consistent with previous studies, which suggest IGF1R is involved in testicular function (1,100).

The association between genes and 15q26 deletion/duplication syndrome remains unclear, warranting further study. The present meta-analysis assessed the association between the growth phenotype and genotype in 15q26-associated syndromes. The present study investigated the association between IGF1R (along with NR2F2, LRRK1 and MEF2A) and short/tall stature phenotype in patients with 15q26 deletion/duplication syndrome. Although not all genes on 15q26 were subjected to meta-analysis, the present study demonstrated that, in addition to IGF1R, other key genes, such as LRRK1, also contributed to the growth abnormality in 15q26-related syndromes. Future studies should further explore the functions and expression patterns of 15q26 deletion/duplication syndrome.

The present study had certain limitations. The CIs may be relatively wide because of a limited sample scale and combined effects from adjacent genes, which led to a lack of statistical power. The lack of validation of the functions of the CNGP cases was another limitation of the present study. Most of the available data were confined to the neonatal period. Therefore, the present cases lack well-established follow-up data, which should be collected in future longitudinal studies. As certain cases present with spontaneous catch-up growth following birth and the application of growth hormone may lead to atypical manifestations of short stature, assessing the true impact on growth becomes challenging, as these factors may not preclude the later manifestation of stunted growth. It may lead to an inaccurate assessment of body size. These factors may introduce potential bias into the findings, which should be interpreted with caution.

Supplementary Material

Information for studies included in the meta-analysis.

Information for studies exluded in the meta-analysis.

Acknowledgements

Not applicable.

Availability of data and materials

The data generated in the present study may be found in the Genome Variation Map in National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences under accession number GVM001225 or at the following URL: ngdc.cncb.ac.cn/gvm/getProjectDetail?project=GVM001225.

Authors' contributions

LY, WZ and FL conceived and designed the study. BW and HW performed whole-exome Sequencing. KY and BL were responsible for CNV analysis. XX and KZ were responsible for clinical data collection. KY, XX and KZ performed the literature review. KY and XX confirm the authenticity of all the raw data. YL, XD, LW, GC, JW and WL analyzed data. KY wrote the manuscript. YL, LW, GC, JW and WL edited the manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References 1

Rudaks

Nicholl

Bratkovic

Barnett

Short stature due to 15q26 microdeletion involving IGF1R: Report of an additional case and review of the literature

Am J Med Genet A155A313931432011

22065603

10.1002/ajmg.a.34310

Kannan

Bodurtha

Hamosh

Jordan

Monochorionic twins with 15q26.3 duplication presenting with selective intrauterine growth restriction and discordant cardiac anomalies: A case report

Mol Genet Genomic Med10e19472022

35795918

10.1002/mgg3.1947

Benbouchta

De Leeuw

Amasdl

Sbiti

Smeets

Sadki

Sefiani

15q26 deletion in a patient with congenital heart defect, growth restriction and intellectual disability: Case report and literature review

Ital J Pediatr471882021

34530895

10.1186/s13052-021-01121-5

Walenkamp

de Muinck Keizer-Schrama

de Mos

Kalf

van Duyvenvoorde

Boot

Kant

White

Losekoot

Den Dunnen

Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification

J Clin Endocrinol Metab93242124252008

18349070

10.1210/jc.2007-1789

Walenkamp

van der Kamp

Pereira

Kant

van Duyvenvoorde

Kruithof

Breuning

Romijn

Karperien

Wit

A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor

J Clin Endocrinol Metab91306230702006

16757531

10.1210/jc.2005-1597

Xiao

Yan

Wang

Yang

Zhou

Protocol of the China neonatal genomes project: An observational study about genetic testing on 100,000 neonates

Pediatr Med4282021

Leffler

Puusepp

Žilina

Zhu

Kuuse

Bain

Burgess

Õunap

Field

Two familial microduplications of 15q26.3 causing overgrowth and variable intellectual disability with normal copy number of IGF1R

Eur J Med Genet592572622016

26689622

10.1016/j.ejmg.2015.12.002

Shamseer

Moher

Clarke

Ghersi

Liberati

Petticrew

Shekelle

Stewart

PRISMA-P Group

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation

BMJ350g76472015

25555855

10.1136/bmj.g7647

Capital Institute of Pediatrics; Coordinating Study Group of Nine Cities on the Physical Growth and Development of Children

Growth standard curves of birth weight, length and head circumference of Chinese newborns of different gestation

Zhonghua Er Ke Za Zhi587387462020

32872714

10.3760/cma.j.cn112140-20200316-00242

(In Chinese)

Zong

Zhang

Height and weight standardized growth charts for Chinese children and adolescents aged 0 to 18 years

Zhonghua Er Ke Za Zhi474874922009

19951507

(In Chinese)

Dong

Liu

Yang

Wang

Liu

Chen

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: A Chinese cohort

J Med Genet575585662020

32005694

10.1136/jmedgenet-2019-106377

Qin

Liu

Yang

Wang

Dong

Zhou

Application of copy number variation screening analysis process based on high-throughput sequencing technology

Chin J Evid Based Pediatr132752792018

Pfundt

Del Rosario

Vissers

LELM

Kwint

Janssen

de Leeuw

Yntema

Nelen

Lugtenberg

Kamsteeg

Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

Genet Med196676752017

28574513

10.1038/gim.2016.163

Gross

Ajay

Rajan

Brown

Bluske

Burns

Chawla

Coffey

Malhotra

Scocchia

Copy-number variants in clinical genome sequencing: Deployment and interpretation for rare and undiagnosed disease

Genet Med21112111302019

30293986

10.1038/s41436-018-0295-y

von der Hagen

Pivarcsi

Liebe

von Bernuth

Didonato

Hennermann

Bührer

Wieczorek

Kaindl

Diagnostic approach to microcephaly in childhood: A two-center study and review of the literature

Dev Med Child Neurol567327412014

24617602

10.1111/dmcn.12425

Orrù

Calloni

Tekes

Huisman

TAGM

Soares

The child with macrocephaly: Differential diagnosis and neuroimaging findings

AJR Am J Roentgenol2108488592018

29470161

10.2214/AJR.17.18693

Hokken-Koelega

ACS

van der Steen

Boguszewski

MCS

Cianfarani

Dahlgren

Horikawa

Mericq

Rapaport

Alherbish

Braslavsky

International consensus guideline on small for gestational age: Etiology and management from infancy to early adulthood

Endocr Rev445395652023

36635911

10.1210/endrev/bnad002

Salomon

Alfirevic

Da Silva Costa

Deter

Figueras

Ghi

Glanc

Khalil

Lee

Napolitano

ISUOG practice guidelines: Ultrasound assessment of fetal biometry and growth

Ultrasound Obstet Gynecol537157232019

31169958

10.1002/uog.20272

Nwosu

Lee

Evaluation of short and tall stature in children

Am Fam Physician785976042008

18788236

Yoon

Hwang

. Microdeletion in the IGF-1 receptor gene of a patient with short stature and obesity: A case report

J Pediatr Endocrinol Metab342552592021

33544498

10.1515/jpem-2020-0478

Chen

Liang

Gong

Yang

Wang

Duan

Pan

Cao

Zhu

The phenotype and rhGH treatment response of ring chromosome 15 syndrome: Case report and literature review

Mol Genet Genomic Med9e18422021

34747577

10.1002/mgg3.1842

Santos

JFD

Acosta

Scheibler

Pitanga

PML

Alves

Meira

JGC

Zanardo

ÉA

Kulikowski

Lima

RLLF

Carvalho

AFL

Case of 15q26-qter deletion associated with a Prader-Willi phenotype

Eur J Med Genet631039552020

32473228

10.1016/j.ejmg.2020.103955

Shao

Wang

Liu

Miao

Clinical, cytogenetic and molecular analyses of a rare case with ring chromosome 15 and review of the literature

Taiwan J Obstet Gynecol599809842020

33218427

10.1016/j.tjog.2020.09.034

Carvalheira

Malinverni

Moysés-Oliveira

Ueta

Cardili

Monteagudo

Mathez

ALG

Verreschi

Maluf

Shida

MEF

The natural history of a man with ovotesticular 46,XX DSD caused by a novel 3-Mb 15q26.2 deletion containing NR2F2 gene

J Endocr Soc3210721132019

31687637

10.1210/js.2019-00241

Kalantari

Karimi

Almadani

Fakhri

Mokhtari

Gourabi

Mohseni Meybodi

Fecundity in an infertile man with r(15)-a challenge to the current paradigm

Reprod Biomed Online362102182018

29223476

10.1016/j.rbmo.2017.10.115

Pelosi

Lapi

Cavalli

Verrotti

Pantaleo

de Martino

Stagi

Bone status in a patient with insulin-like growth factor-1 receptor deletion syndrome: Bone quality and structure evaluation using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and quantitative ultrasonography

Front Endocrinol (Lausanne)82272017

28936199

10.3389/fendo.2017.00227

O'Riordan

McGrath

Sharif

Murphy

Franklin

Lynch

O'Grady

Expanding the clinical spectrum of chromosome 15q26 terminal deletions associated with IGF-1 resistance

Eur J Pediatr1761371422017

27826649

10.1007/s00431-016-2802-y

Cannarella

Mattina

Condorelli

Mongioì

Pandini

La Vignera

Calogero

Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function

Endocr Connect65285392017

28899882

10.1530/EC-17-0158

Verhoeven

Egger

Knegt

Zuydam

Kleefstra

Absence epilepsy and the CHD2 gene: An adolescent male with moderate intellectual disability, short-lasting psychoses, and an interstitial deletion in 15q26.1-q26.2

Neuropsychiatr Dis Treat12113511392016

27274247

10.2147/NDT.S102272

Reiss

Ahern

Sandstrom

Wilkins-Haug

Recurrent enlarged nuchal translucency: First trimester presentation of a familial 15q26→qter deletion

Am J Med Genet A167A6126162015

25691414

10.1002/ajmg.a.36913

Clayton

Vasudevan

Greening

Wardhaugh

Shaw

Kelnar

Kirk

Högler

Recombinant human growth hormone therapy in children with chromosome 15q26 deletion. Horm Res Paediatr: Apr 22, 2015 (Epub ahead of print).

Kamien

Harraway

Lundie

Smallhorne

Gibbs

Heath

Fullerton

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy

Am J Med Genet A164A7827882014

24357335

10.1002/ajmg.a.36345

Courage

Houge

Gallati

Schjelderup

Rieubland

15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity

Eur J Med Genet575205232014

24932903

10.1016/j.ejmg.2014.06.003

Schilter

Reis

Schneider

Bardakjian

Abdul-Rahman

Kozel

Zimmerman

Broeckel

Semina

Whole-genome copy number variation analysis in anophthalmia and microphthalmia

Clin Genet844734812013

23701296

10.1111/cge.12202

Lalani

Ware

Wang

Zapata

Tian

Franco

Jiang

Bucasas

Scott

Campeau

MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development

Hum Mol Genet22433943482013

23773997

10.1093/hmg/ddt283

Witsch

Szafranski

Chen

Immken

Simpson Patel

Hixson

Cheung

Stankiewicz

Schaaf

Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay

Eur J Hum Genet21130413072013

23486542

10.1038/ejhg.2013.42

Spengler

Begemann

Ortiz Brüchle

Baudis

Denecke

Kroisel

Oehl-Jaschkowitz

Schulze

Raabe-Meyer

Spaich

Molecular karyotyping as a relevant diagnostic tool in children with growth retardation with Silver-Russell features

J Pediatr1619339422012

22683032

10.1016/j.jpeds.2012.04.045

Capelli

Krepischi

Gurgel-Giannetti

Mendes

Rodrigues

Varela

Koiffmann

Rosenberg

Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency

Eur J Med Genet551321342012

22178256

10.1016/j.ejmg.2011.10.004

Guilherme

Meloni Vde

Takeno

Pellegrino

Brunoni

Kulikowski

Melaragno

Twenty-year cytogenetic and molecular follow-up of a patient with ring chromosome 15: A case report

J Med Case Rep62832012

22958471

10.1186/1752-1947-6-283

Dateki

Fukami

Tanaka

Sasaki

Moriuchi

Ogata

Identification of chromosome 15q26 terminal deletion with telomere sequences and its bearing on genotype-phenotype analysis

Endocr J581551592011

21242650

10.1507/endocrj.k10e-251

Dhamija

Breningstall

Wong-Kisiel

Dolan

Hirsch

Wirrell

Microdeletion of chromosome 15q26.1 in a child with intractable generalized epilepsy

Pediatr Neurol4560622011

21723464

10.1016/j.pediatrneurol.2011.02.002

Chen

Lin

Hsu

Liu

Chern

Chen

Chromosome 15q overgrowth syndrome: Prenatal diagnosis, molecular cytogenetic characterization, and perinatal findings in a fetus with dup(15)(q26.2q26.3)

Taiwan J Obstet Gynecol503593652011

22030053

10.1016/j.tjog.2011.07.004

Jezela-Stanek

Kucharczyk

Pelc

Chrzanowska

Krajewska-Walasek

Minimal clinical findings in a patient with 15qter microdeletion syndrome: Delineation of the associated phenotype

Am J Med Genet A158A9229262012

22344789

10.1002/ajmg.a.34440

Rujirabanjerd

Suwannarat

Sripo

Dissaneevate

Permsirivanich

Limprasert

De novo subtelomeric deletion of 15q associated with satellite translocation in a child with developmental delay and severe growth retardation

Am J Med Genet A143A2712762007

17236205

10.1002/ajmg.a.31581

Choi

Kang

Kim

Hong

Jin

Lee

Park

Lee

Seo

Yoo

Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure

J Clin Endocrinol Metab96E130E1342011

20962017

10.1210/jc.2010-1789

Veenma

DCM

Eussen

Govaerts

LCP

de Kort

SWK

Odink

Wouters

Hokken-Koelega

ACS

de Klein

Phenotype-genotype correlation in a familial IGF1R microdeletion case

J Med Genet474924982010

19955558

10.1136/jmg.2009.070730

Cody

Heard

Hale

Identification of two novel chromosome regions associated with isolated growth hormone deficiency

J Pediatr Endocrinol Metab23115911642010

21284329

10.1515/jpem.2010.181

Bruce

Hannula-Jouppi

Puoskari

Fransson

Simola

Lipsanen-Nyman

Kere

Submicroscopic genomic alterations in Silver-Russell syndrome and Silver-Russell-like patients

J Med Genet478168222010

19752157

10.1136/jmg.2009.069427

Lin

Lee

Hung

Tsai

Lin

Hsieh

Tung

Niu

Hsu

Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver-Russell syndrome

Am J Med Genet A152A252125282010

20830799

10.1002/ajmg.a.33629

Ester

van Duyvenvoorde

de Wit

Broekman

Ruivenkamp

Govaerts

Wit

Hokken-Koelega

Losekoot

Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype

J Clin Endocrinol Metab94471747272009

19864454

10.1210/jc.2008-1502

Veredice

Bianco

Contaldo

Orteschi

Stefanini

Battaglia

Lettori

Guzzetta

Zollino

Early onset myoclonic epilepsy and 15q26 microdeletion: Observation of the first case

Epilepsia50181018152009

19486360

10.1111/j.1528-1167.2009.02078.x

Gervasini

Pfundt

Castronovo

Russo

Roversi

Masciadri

Milani

Zampino

Selicorni

Schoenmakers

Larizza

Search for genomic imbalances in a cohort of 24 Cornelia de Lange patients negative for mutations in the NIPBL and SMC1L1 genes

Clin Genet745315382008

18798846

10.1111/j.1399-0004.2008.01086.x

Davidsson

Collin

Björkhem

Soller

Array based characterization of a terminal deletion involving chromosome subband 15q26.2: An emerging syndrome associated with growth retardation, cardiac defects and developmental delay

BMC Med Genet922008

18194513

10.1186/1471-2350-9-2

Nimmakayalu

Mercer

Andersson

Emanuel

Characterization of a cryptic 3.3 Mb deletion in a patient with a ‘balanced t(15;22) translocation’ using high density oligo array CGH and gene expression arrays

Am J Med Genet A146A3683752008

18203177

10.1002/ajmg.a.32116

Rump

Dijkhuizen

Sikkema-Raddatz

Lemmink

Vos

Verheij

van Ravenswaaij

Drayer's syndrome of mental retardation, microcephaly, short stature and absent phalanges is caused by a recurrent deletion of chromosome 15(q26.2->qter)

Clin Genet744554622008

18651844

10.1111/j.1399-0004.2008.01064.x

Klaassens

Galjaard

Scott

Brüggenwirth

van Opstal

Fox

Higgins

Cohen-Overbeek

Schoonderwaldt

Lee

Prenatal detection and outcome of congenital diaphragmatic hernia (CDH) associated with deletion of chromosome 15q26: Two patients and review of the literature

Am J Med Genet A143A220422122007

17702015

10.1002/ajmg.a.31892

Hatem

Meriam

Walid

Adenen

Moez

Ali

Molecular characterization of a ring chromosome 15 in a fetus with intra uterine growth retardation and diaphragmatic hernia

Prenat Diagn274714742007

17380471

10.1002/pd.1707

Kant

Kriek

Walenkamp

Hansson

van Rhijn

Clayton-Smith

Wit

Breuning

Tall stature and duplication of the insulin-like growth factor I receptor gene

Eur J Med Genet501102007

17056309

10.1016/j.ejmg.2006.03.005

López

Bafalliu

Bernabé

García

Costa

Guillén-Navarro

Prenatal diagnosis of de novo deletions of 8p23.1 or 15q26.1 in two fetuses with diaphragmatic hernia and congenital heart defects

Prenat Diagn265775802006

16700088

10.1002/pd.1468

Pinson

Perrin

Plouzennec

Parent

Metz

Collet

Le Bris

Douet-Guilbert

Morel

De Braekeleer

Detection of an unexpected subtelomeric 15q26.2 ->qter deletion in a little girl: clinical and cytogenetic studies

Am J Med Genet A138A1601652005

16114049

10.1002/ajmg.a.30939

Bhakta

Marlin

Shen

Fernandes

Terminal deletion of chromosome 15q26.1: Case report and brief literature review

J Perinatol254294322005

15843813

10.1038/sj.jp.7211301

Hammer

Kutsche

Haag

Ullrich

Sudbrak

Willig

Braulke

Kubler

Mono-allelic expression of the IGF-I receptor does not affect IGF responses in human fibroblasts

Eur J Endocrinol1515215292004

15476454

10.1530/eje.0.1510521

Biggio

JR Jr

Descartes

Carroll

Holt

Congenital diaphragmatic hernia: Is 15q26.1-26.2 a candidate locus?

Am J Med Genet A126A1831852004

15057983

10.1002/ajmg.a.20464

Okubo

Siddle

Firth

O'Rahilly

Wilson

Willatt

Fukushima

Takahashi

Petry

Saukkonen

Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene

J Clin Endocrinol Metab88598159882003

14671200

10.1210/jc.2002-021080

Harada

Shimokawa

Nagai

Kato

Kondoh

Niikawa

Matsumoto

A 4-Mb critical region for intrauterine growth retardation at 15q26

Clin Genet623403422002

12372065

10.1034/j.1399-0004.2002.620416.x

Tönnies

Schulze

Hennies

Neumann

Keitzer

Neitzel

De novo terminal deletion of chromosome 15q26.1 characterised by comparative genomic hybridisation and FISH with locus specific probes

J Med Genet386176212001

11565548

10.1136/jmg.38.9.617

Siebler

Lopaczynski

Terry

Casella

Munson

De Leon

Phang

Blakemore

McEvoy

Kelley

Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15

J Clin Endocrinol Metab80344734571995

8530582

10.1210/jcem.80.12.8530582

Peoples

Milatovich

Francke

Hemizygosity at the insulin-like growth factor I receptor (IGF1R) locus and growth failure in the ring chromosome 15 syndrome

Cytogenet Cell Genet702282341995

7789178

10.1159/000134040

Tamura

Tohma

Ohta

Soejima

Harada

Abe

Niikawa

Ring chromosome 15 involving deletion of the insulin-like growth factor 1 receptor gene in a patient with features of Silver-Russell syndrome

Clin Dysmorphol21061131993

7506614

Roback

Barakat

Dev

Mbikay

Chrétien

Butler

An infant with deletion of the distal long arm of chromosome 15 (q26.1-qter) and loss of insulin-like growth factor 1 receptor gene

Am J Med Genet3874791991

1849352

10.1002/ajmg.1320380117

Poot

Verrijn Stuart

van Daalen

van Iperen

van Binsbergen

Hochstenbach

Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases

Eur J Med Genet563463502013

23603061

10.1016/j.ejmg.2013.04.001

Slavotinek

Moshrefi

Davis

Leeth

Schaeffer

Burchard

Shaw

James

Ptacek

Pennacchio

Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: Mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1-15q26.2

Eur J Hum Genet1499910082006

16736036

10.1038/sj.ejhg.5201652

Kawashima-Sonoyama

Wada

Yamamoto

Fujimoto

Namba

Taketani

Clinical characteristics of and growth hormone treatment effects on short stature with type 1 insulin-like growth factor receptor (IGF1R) gene alteration

Endocr J716876942024

38710621

10.1507/endocrj.EJ23-0680

Dincer

Ozdemir

Cetincelik

Ucar

Drayer syndrome due to chromosome 15q26.3 deletion: Response to growth hormone treatment

Sisli Etfal Hastan Tip Bul585215232024

39816431

10.14744/SEMB.2024.01879

Arroyo-Ruiz

Urbano-Ruiz

García-Berrocal

Marcos-Vadillo

Isidoro-García

Martín-Alonso

Bajo-Delgado

Prieto-Matos

López-Siguero

Clinical and genetic characterization of a cohort of small-for-gestational-age patients: Cost-effectiveness of whole-exome sequencing and effectiveness of treatment with GH

J Clin Med1340062024

39064046

10.3390/jcm13144006

Sivakumaran

Grebe

15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature

Am J Med Genet A191239223972023

37434556

10.1002/ajmg.a.63350

Solmaz

Durmaz

Braekeleer

Cogulu

Ozkinay

A further patient of pure 15q deletion: Clinical and molecular cytogenetic findings

Genet Couns27182016

27192887

Nakamura

Makita

Okamoto

Nagaya

Hayashi

Sugimoto

Manabe

Taketazu

Kajino

Fujieda

5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects

Eur J Med Genet543543562011

21172461

10.1016/j.ejmg.2010.12.004

Yuan

Yin

Tao

Wang

Gao

Function of insulin-like growth factor 1 receptor in cancer resistance to chemotherapy

Oncol Lett1541472018

29285186

10.3892/ol.2017.7276

Holzenberger

Leneuve

Hamard

Ducos

Perin

Binoux

Le Bouc

A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit

Endocrinology141255725662000

10875258

10.1210/endo.141.7.7550

Nagai

Shimokawa

Harada

Sakazume

Ohashi

Matsumoto

Obata

Yoshino

Murakami

Murai

Postnatal overgrowth by 15q-trisomy and intrauterine growth retardation by 15q-monosomy due to familial translocation t(13;15): Dosage effect of IGF1R?

Am J Med Genet1131731772002

12407708

10.1002/ajmg.10717

Fujimoto

Kawashima Sonoyama

Hamajima

Kumura

Miyahara

Nishimura

Adachi

Nanba

Hanaki

Kanzaki

Heterozygous nonsense mutations near the C-terminal region of IGF1R in two patients with small-for-gestational-age-related short stature

Clin Endocrinol (Oxf)838348412015

25866162

10.1111/cen.12791

Prontera

Micale

Verrotti

Napolioni

Stangoni

Merla

A new homozygous IGF1R variant defines a clinically recognizable incomplete dominant form of SHORT syndrome

Hum Mutat36104310472015

26252249

10.1002/humu.22853

Fang

Cho

Derr

Rosenfeld

Hwa

Cowell

Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R)

J Clin Endocrinol Metab97E243E2472012

22130793

10.1210/jc.2011-2142

Yang

Sun

Wei

Liu

Zhang

Luo

IGF1R variants in patients with growth impairment: Four novel variants and genotype-phenotype correlations

J Clin Endocrinol Metab103393939442018

30053089

10.1210/jc.2017-02782

Abuzzahab

Schneider

Goddard

Grigorescu

Lautier

Keller

Kiess

Klammt

Kratzsch

Osgood

IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation

N Engl J Med349221122222003

14657428

10.1056/NEJMoa010107

Walenkamp

MJE

Robers

JML

Wit

Zandwijken

GRJ

van Duyvenvoorde

Oostdijk

Hokken-Koelega

ACS

Kant

Losekoot

Phenotypic features and response to GH treatment of patients with a molecular defect of the IGF-1 receptor

J Clin Endocrinol Metab104315731712019

30848790

10.1210/jc.2018-02065

Giabicani

Willems

Steunou

Chantot-Bastaraud

Thibaud

Abi Habib

Azzi

Lam

Bérard

Bony-Trifunovic

Increasing knowledge in IGF1R defects: Lessons from 35 new patients

J Med Genet571601682020

31586944

10.1136/jmedgenet-2019-106328

Bellucco

Favilla

Perrone

Melaragno

Partial 5p Gain and 15q loss in three patients from a family with a t(5;15)(p13.3;q26.3) translocation. Cytogenet Genome Res: 1-8, 2020 (Epub ahead of print).

Szabó

Czakó

Hadzsiev

Duga

Bánfai

Komlósi

Melegh

Small supernumerary marker chromosome 15 and a ring chromosome 15 associated with a 15q26.3 deletion excluding the IGF1R gene

Am J Med Genet A1764434492018

29226546

10.1002/ajmg.a.38566

Amberger

Bocchini

Schiettecatte

Scott

Hamosh

OMIM.org

Online mendelian inheritance in man (OMIM^®), an online catalog of human genes and genetic disorders

Nucleic Acids Res43D789D7982015

25428349

10.1093/nar/gku1205

Xiong

Wang

Jiang

Pang

Liu

Zhong

Liu

MEF2A alters the proliferation, inflammation-related gene expression profiles and its silencing induces cellular senescence in human coronary endothelial cells

BMC Mol Biol2082019

30885136

10.1186/s12867-019-0125-z

Moustafa

Hashemi

Brar

Grigull

SHS

Williams

Schmitt-Ulms

McDermott

The MEF2A transcription factor interactome in cardiomyocytes

Cell Death Dis142402023

37019881

10.1038/s41419-023-05665-8

Ganapathi

Matsuoka

March

Brokamp

Benito-Sanz

White

Lachlan

Ahimaz

Sewda

Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays

Eur J Hum Genet31111711242023

37500725

10.1038/s41431-023-01434-5

Salo-Mullen

Lynn

Wang

Walsh

Gopalan

Shia

Tran

Man

McBride

Schattner

Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome

Fam Cancer1771772018

28555354

10.1007/s10689-017-0006-x

Pizza

Picillo

Onore

Scutifero

Passamano

Nigro

Politano

Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: Case report and review literature

Acta Myol4224302023

37091526

10.36185/2532-1900-246

Al-Qattan

Rahbeeni

Al-Hassnan

Jarman

Rafique

Mahabbat

Alsufayan

FAS

Chromosome 16p13.3 contiguous gene deletion syndrome including the SLX4, DNASE1, TRAP1, and CREBBP genes presenting as a relatively mild rubinstein-taybi syndrome phenotype: A case report of a saudi boy

Case Rep Genet202061430502020

32181026

10.1155/2020/6143050

Pinnaro

Henry

Major

Parida

DesJardin

Manak

Darbro

Candidate modifier genes for immune function in 22q11.2 deletion syndrome

Mol Genet Genomic Med8e10572020

31830774

10.1002/mgg3.1057

Díaz Del Moral

Benaouicha

Muñoz-Chápuli

Carmona

The insulin-like growth factor signalling pathway in cardiac development and regeneration

Int J Mol Sci232342021

35008660

10.3390/ijms23010234

100

Cannarella

Condorelli

La Vignera

Calogero

Effects of the insulin-like growth factor system on testicular differentiation and function: A review of the literature

Andrology6392018

29195026

10.1111/andr.12444

Figure 1

Flow chart of the literature screening and reviewing procedure using PubMed and case selection process for meta-analysis. CNV, copy number variation.

Figure 2

Chromosome locations of deletion and duplication cases with specific positions in UCSC genome browser assembly (GRCh37/hg19). Orange, candidate genes; dark blue, duplication cases with tall stature; light blue, duplication cases without tall stature; dark green, deletion cases with short stature; light green, deletion cases without short stature. UCSC, University of California, Santa Cruz.

Figure 3

Meta-analysis of the roles of candidate genes in 15q26 deletion syndrome. IGF1R, insulin-like growth factor 1 receptor; LRRK1, leucine-rich repeat kinase 1; MEF2A, myocyte enhancer factor 2A; NR2F2, nuclear receptor subfamily 2 group F member 2; M-H, Mantel-Haenszel.

Figure 4

Meta-analysis of the roles of candidate genes in 15q26 duplication syndrome. IGF1R, insulin-like growth factor 1 receptor; LRRK1, leucine-rich repeat kinase 1; MEF2A, myocyte enhancer factor 2A; NR2F2, nuclear receptor subfamily 2 group F member 2; M-H, Mantel-Haenszel.

Table I

Clinical and genetic information of patients enrolled in the China Neonatal Genomes Project.

A, Duplication
Patient no.	Sex	Band	Length, kb	IGF1R involvement	LRRK1 involvement	MEF2A involvement	NR2F2 involvement	SGA/short stature	LGA/tall stature	Other clinical features
1	F	15q26.1/15q26.3	4209.50/2600.49	Yes	Yes	Yes	No	+	-	Café au lait spots, seizure, microcephaly, developmental delay and congenital heart disease
2	M	15q26.1-q26.3	10947.50	Yes	Yes	Yes	Yes	-	+	Congenital upper and lower limb deformity and obesity
3	M	15q26.1	4209.50	No	No	No	No	-	-	Congenital heart disease and developmental delay
B, Deletion
Patient no.	Sex	Band	Length, kb	IGF1R involvement	LRRK1 involvement	MEF2A involvement	NR2F2 involvement	SGA/short stature	LGA/tall stature	Other clinical features
4	M	15q26.3	2600.49	Yes	Yes	Yes	No	+	-	Dislocation of hip joint, café au lait spots, developmental delay
5	F	15q26.3	3856.47	Yes	Yes	Yes	No	+	-	Congenital hip dysplasia
6	M	15q26.3	3856.47	Yes	Yes	Yes	No	+	-	Hypotonia and cryptorchidism
7	M	15q26.3	2600.49	Yes	Yes	Yes	No	+	-	Cryptorchidism, developmental delay, congenital heart disease and squint
8	F	15q26.3	1280.61	No	Yes	No	No	+	-	Developmental delay
9	F	15q26.3	1203.19	No	Yes	No	No	+	-	-
10	M	15q26.1	4216.30	No	No	No	No	+	-	Developmental delay and congenital coxa vara

IGF1R, insulin-like growth factor 1 receptor; LRRK1, leucine-rich repeat kinase 1; MEF2A, myocyte enhancer factor 2A; NR2F2, nuclear receptor subfamily 2 group F member 2; SGA, Small for gestational age; LGA, Large for gestational age; M, male; F, female; +, positive; -, negative.

Table II

Demographic information and clinical features of patients from the literature.

Characteristic	15q26 deletion (n=78)	15q26 duplication (n=10)	P-value
Age (%)			0.007^a
0-1 months	7/78 (9.0)	3/10 (30.0)
>1 month-3 years	22/78 (28.2)	0/10 (0.0)
>3-18 years	39/78 (50.0)	3/10 (30.0)
>18 years	10/78 (12.8)	4/10 (40.0)
Female (%)	54/78 (69.2)	3/8 (37.5)	0.157^b
SGA (%)	43/64 (67.2)	1/8 (12.5)	0.009^b
LGA (%)	0/64 (0.0)	2/8 (25.0)	0.011^a
Short stature (%)	58/71 (81.7)	0/7 (0.0)	<0.001^b
Tall stature (%)	0/71 (0.0)	4/7 (57.1)	<0.001^a
Cardiac malformation (%)	29/75 (38.7)	1/8 (12.5)	0.281^b
Developmental delay (%)	49/61 (80.3)	1/6 (16.7)	0.003^b
Microcephaly (%)	39/66 (59.1)	0/7 (0.0)	0.010^b
Macrocephaly (%)	0/66 (0.0)	2/7 (28.6)	0.009^a
Facial abnormality (%)	65/77 (84.4)	10/10 (100.0)	0.391^b
Speech development delay (%)	31/50 (62.0)	5/6 (83.3)	0.562^b
Hand/foot/skeleton malformation (%)	55/76 (72.4)	6/7 (85.7)	0.750^b

^aFisher's exact test;

^bcontinuity correction. SGA, small for gestational age; LGA, Large for gestational age.