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 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.

A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test

2015 ◽  
Vol 147 (2-3) ◽  
pp. 103-110 ◽  
Author(s):  
Valérie Malan ◽  
Jean-Michel Lapierre ◽  
Matthieu Egloff ◽  
Didier Goidin ◽  
Marie-Paule Beaujard ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Clinical Setting ◽  
Ethical Issues ◽  
Genetic Test ◽  
Copy Number Variants ◽  
Clinical Impact ◽  
Added Value ◽  
Comparative Genomic ◽  
Genomic Imbalances ◽  
Pathogenic Cnvs

Cytogenetic microarray analysis is now the first-tier genetic test used in a postnatal clinical setting to explore genomic imbalances in individuals with developmental disability and/or birth defects. However, in a prenatal setting, this technique is not widely implemented, largely because the clinical impact of some copy number variants (CNVs) remains difficult to assess. This limitation is especially true in France where termination of pregnancy for medical reasons may be performed at any stage of gestation. During a period of 15 months, we investigated 382 fetuses presenting with ultrasound anomalies, using a customized microarray designed to avoid the detection of CNVs raising challenges for genetic counseling. After excluding common aneuploidies, 20/374 (5.3%) fetuses had a pathogenic CNV, among which 12/374 (3.2%) could have been detected by karyotyping, whereas 8/374 (2.1%) were cryptic. Within these 374 cases, 300 were ongoing pregnancies at the time of array comparative genomic hybridization (aCGH) testing. For these pregnancies, we detected 18/300 (6%) pathogenic CNVs, among which 6/300 (2%) were cryptic. Using this approach, only 2/300 (0.6%) of the detected CNVs raised difficulties for genetic counseling. This study confirms the added value of this strategy in a prenatal clinical setting to minimize ethical issues for genetic counseling while enhancing the detection of genomic imbalances.

scholarly journals Critical exon indexing improves clinical interpretation of copy number variants in neurodevelopmental disorders

2019 ◽  
Vol 5 (6) ◽  
pp. e378 ◽  
Author(s):  
E. Robert Wassman ◽  
Karen S. Ho ◽  
Diana Bertrand ◽  
Kyle W. Davis ◽  
Megan M. Martin ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Relevant Literature ◽  
Copy Number Variants ◽  
Mendelian Inheritance ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Variants Of Unknown Significance ◽  
Pathogenic Cnvs ◽  
Highly Correlated

ObjectiveTo evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.MethodsCritical exon indexing (CEI) was used to identify genes with critical exons (CEGs) from clinically reported CNVs, which may contribute to neurodevelopmental disorders (NDDs). The 742 pathogenic CNVs and 1,363 variants of unknown significance (VUS) identified by chromosomal microarray analysis in 5,487 individuals with NDDs were subjected to CEI to identify CEGs. CEGs identified in a subsequent random series of VUS were evaluated for relevance to CNV interpretation.ResultsCEI identified a total of 2,492 unique CEGs in pathogenic CNVs and 953 in VUS compared with 259 CEGs in 6,965 CNVs from 873 controls. These differences are highly significant (p < 0.00001) whether compared as frequency, average, or normalized by CNV size. Twenty-one percent of VUS CEGs were not represented in Online Mendelian Inheritance in Man, highlighting limitations of existing resources for identifying potentially impactful genes within CNVs. CEGs were highly correlated with other indices and known pathways of relevance. Separately, 136 random VUS reports were reevaluated, and 76% of CEGs had not been commented on. In multiple cases, further investigation yielded additional relevant literature aiding interpretation. As one specific example, we discuss GTF2I as a CEG, which likely alters interpretation of several reported duplication VUS in the Williams-Beuren region.ConclusionsApplication of CEI to CNVs in individuals with NDDs can identify genes of potential clinical relevance, aid laboratories in effectively searching the clinical literature, and support the clinical reporting of poorly annotated VUS.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

scholarly journals Copy Number Variation of Multiple Genes in SAPHO Syndrome

2019 ◽  
Vol 47 (9) ◽  
pp. 1323-1329
Author(s):  
Changlong Guo ◽  
Xin Tian ◽  
Feifei Han ◽  
Lihong Liu ◽  
Jianen Gao ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Candidate Genes ◽  
Copy Number ◽  
Nuclear Family ◽  
Sapho Syndrome ◽  
Unknown Etiology ◽  
Comparative Genomic ◽  
Number Variation ◽  
And Control ◽  
Control Samples

Objective.SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a type of rare chronic aseptic inflammation of unknown etiology. To date, no research to our knowledge has reported copy number variation (CNV) of genes that could affect predisposition to SAPHO syndrome. We investigated the association between CNV profile and SAPHO syndrome.Methods.We used array comparative genomic hybridization (CGH) to screen for CNV in a nuclear family including 2 patients and a healthy control. We then validated the copy numbers of candidate genes found in the array CGH assay and other candidate genes by TaqMan real-time PCR in 360 case and control samples.Results.Ten regions from 8 chromosomes were found to have abnormal gene copies in the nuclear family, so the CNV of candidate genes (ADAM5, CSF2RA, IL3RA, and 9 other genes) were tested by TaqMan PCR. Significant copy number loss of CSF2RA (p = 0.000) and NOD2 (p = 0.005), and significant copy number gain of MEGF6 (p = 0.002) and ADAM5 (p = 0.000) were seen in patients with SAPHO compared with controls at the a = 0.05 level. There were no differences in the other 8 candidate genes between patient and control samples (p > 0.05).Conclusion.Our study established the first association between CNV in CSF2RA, NOD2, MEGF6, and ADAM5 and SAPHO syndrome. These findings may offer insight into the pathogenesis of SAPHO and provide the basis for improved diagnosis and treatment.

Molecular karyotyping in routine diagnostics – a view back and forth1)

2013 ◽  
Vol 36 (5) ◽  
Author(s):  
Uwe Heinrich ◽  
Meike Gabert ◽  
Imma Rost
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Uniparental Disomy ◽  
Simultaneous Detection ◽  
Molecular Karyotyping ◽  
Comparative Genomic ◽  
Detection Rates ◽  
Routine Diagnostics ◽  
Indispensable Tool

AbstractSince its introduction in the routine diagnostics of patients with mental retardation/developmental delay, array-comparative genomic hybridization (aCGH) has become an indispensable tool for the detection of clinically relevant copy number variants (CNVs). Despite the current tendency for higher resolution arrays, the growing number of public internet databases as well as better calling algorithms allow save reporting and a better classification of CNVs. The application of combined aCGH plus single nucleotide polymorphism (SNP) arrays will increase detection rates by revealing copy number neutral changes, such as uniparental disomy. In the future, next generation sequencing techniques will lead to a further increase in resolution with the simultaneous detection of unbalanced and even balanced chromosomal aberrations.

Sign in / Sign up

Export Citation Format

Share Document