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.
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.
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).
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.
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).
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.
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.
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.
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).
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.
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.
Not applicable.
Funding: No funding was received.
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.
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 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 present
study conformed to the principles of the Helsinki Declaration.
Not applicable.
The authors declare that they have no competing
interests.
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