scholarly journals Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

2014 ◽  
Vol 171 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Ana P M Canton ◽  
Sílvia S Costa ◽  
Tatiane C Rodrigues ◽  
Debora R Bertola ◽  
Alexsandra C Malaquias ◽  
...  
Keyword(s):  
Short Stature ◽  
Candidate Genes ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Comparative Genomic ◽  
Growth Disorders ◽  
Genomic Regions

BackgroundThe etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders.ObjectiveTo analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.Patients and methodsA total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature.ResultsIn 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation.ConclusionPathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

scholarly journals Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

2017 ◽  
Vol 89 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Thais K. Homma ◽  
Ana C.V. Krepischi ◽  
Tatiane K. Furuya ◽  
Rachel S. Honjo ◽  
Alexsandra C. Malaquias ◽  
...  
Keyword(s):  
Short Stature ◽  
Copy Number ◽  
Single Nucleotide Polymorphism Array ◽  
Copy Number Variants ◽  
Chromosomal Microarray ◽  
Unknown Etiology ◽  
Comparative Genomic ◽  
Growth Disorders ◽  
Genomic Imbalances ◽  
Pathogenic Cnvs

Background/Aims: Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. Methods: We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. Results: We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. Conclusion: CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.

scholarly journals Systematic analysis of copy number variation associated with congenital diaphragmatic hernia

2018 ◽  
Vol 115 (20) ◽  
pp. 5247-5252 ◽  
Author(s):  
Qihui Zhu ◽  
Frances A. High ◽  
Chengsheng Zhang ◽  
Eliza Cerveira ◽  
Meaghan K. Russell ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Candidate Genes ◽  
Birth Defects ◽  
Diaphragmatic Hernia ◽  
Copy Number ◽  
Large Scale ◽  
De Novo ◽  
Comparative Genomic ◽  
High Morbidity ◽  
Systematic Analysis

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B. We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

scholarly journals Copy Number Variants in Short Children Born Small for Gestational Age

2014 ◽  
Vol 82 (5) ◽  
pp. 310-318 ◽  
Author(s):  
Jan M. Wit ◽  
Hermine A. van Duyvenvoorde ◽  
Jan B. van Klinken ◽  
Janina Caliebe ◽  
Cathy A.J. Bosch ◽  
...  
Keyword(s):  
Gestational Age ◽  
Small For Gestational Age ◽  
Copy Number ◽  
Copy Number Variants ◽  
Short Children

High Resolution Array-Based CGH and SNP Studies of AML Genomes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 107-107
Author(s):  
Matthew J. Walter ◽  
R. Ries ◽  
X. Li ◽  
W. Shannon ◽  
J. Payton ◽  
...  
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Neutral Loss ◽  
Copy Number Variants ◽  
Uniparental Disomy ◽  
Cell Receptor ◽  
Homozygous Deletion ◽  
Comparative Genomic ◽  
Snp Arrays ◽  
Gains And Losses

Abstract To test if small deletions or amplifications (ie. below the resolution of cytogenetics) exist in bone marrow-derived tumor DNA from acute myeloid leukemia (AML) patients (pts), we used a dense tiling path array comparative genomic hybridization (aCGH) platform consisting of 386,165 unique oligomers spaced evenly at ∼6Kb intervals across the genome. We analyzed 144 adult de novo AML pts; 64 had normal karyotypes, and 80 had 1 or 2 clonal aberrations. Similar numbers of FAB M0/1, M2, M3, and M4 pts were included, and all samples had >30% blasts (median=72%). To generate a cancer-free control set of data, we also analyzed 23 DNA samples from normal individuals matched for age and ethnicity, and with no history of cancer. Both the tumor and cancer-free control DNA samples were co-hybridized with a pool of control DNAs from blood of 4 healthy young males. To define the sensitivity and specificity of the aCGH platform, we examined its ability to detect cytogenetically defined chromosome gains and losses. Of the 33 gains and losses present in >20% of metaphases, 29 (88%) were detected by aCGH. Of the 20 gains and losses present in ≤20% of metaphases, aCGH detected only 5 (25%). Three of 63 (4.8%) balanced translocations [t(15;17), t(8;21), t(9;11)] were detected using aCGH, indicating that breakpoints of some translocations contained small deletions. Further, we identified many previously described germline copy number variants (CNVs) in both the AML pts and cancer-free controls. To improve our ability to define even smaller somatic microdeletions and amplifications, we tested 20 AML pts using CGH arrays containing 1.5 million probes per genome (average probe spacing 1.5 Kb). To preclude detection of germline CNVs, the higher resolution CGH experiments were performed comparing tumor and skin-derived DNA from the same patient. These same sample pairs were also analyzed individually with the Affymetrix 500K SNP arrays. Using stringent criteria to define abnormal segments, we identified 64 altered loci in the 20 AML pts that were not apparent cytogenetically, and that contained ≥1 gene. SNP arrays confirmed aCGH findings in 7/9 loci >100 Kb, and in 1/55 loci <100 Kb in size. In addition, SNP arrays revealed copy number neutral loss of heterozygosity of the 11p arm in 2/20 AML pts, indicating partial uniparental disomy (UPD) involving this region. We also detected somatic deletions in the T cell receptor (TCR) (n=3/20) and immunoglobulin heavy chain (n=1/20) genes, including a homozygous deletion measuring 4.3 Kb in size. The remaining loci identified with the 1.5M oligo aCGH platform were validated using quantitative PCR with matched tumor and germline DNA. Only 5/60 putative calls were validated using this approach, and include a deletion of IGFBP2, and amplifications of CROP, CPEB4, HOMER1, and ZNF148. In summary, 13 loci containing genes have been validated by SNP arrays or qPCR. No recurrent deletions or amplifications were found in the 20 AML pts. Thus, an additional 74 AML pts are being screened for evidence of recurrence at these loci. Our data suggest that an ultra-dense platform may be required to detect the majority of somatic copy number changes in AML genomes, and that UPD is relatively rare in AML pts, occurring in ∼10% of pts, and recurrent only in the 11p region.

scholarly journals Three years of growth hormone therapy in children born small for gestational age: results from the ANSWER Program

2018 ◽  
Vol 7 (10) ◽  
pp. 1096-1104 ◽  
Author(s):  
Robert Rapaport ◽  
Peter A Lee ◽  
Judith L Ross ◽  
Paul Saenger ◽  
Vlady Ostrow ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Growth Failure ◽  
Hormone Deficiency ◽  
Birth Size ◽  
Growth Disorders ◽  
Gh Therapy ◽  
The Impact

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin Studies: Web-Enabled Research (ANSWER) Program was analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/L), SGA with peak GH <10 ng/mL (20 mIU/L), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.

scholarly journals Copy number variation in pediatric multiple sclerosis

2012 ◽  
Vol 19 (8) ◽  
pp. 1014-1021 ◽  
Author(s):  
JP McElroy ◽  
LB Krupp ◽  
BA Johnson ◽  
JL McCauley ◽  
Z Qi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Early Onset ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Pediatric Multiple Sclerosis ◽  
Reported Study ◽  
Number Variation ◽  
Genomic Regions

Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient’s disease course and prognosis.

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