Molecular Characterization of a Familial 13.6-Mb 20p11.1p12.1 Duplication without Clinical Consequence

2019 ◽  
Vol 157 (3) ◽  
pp. 141-147
Author(s):  
Julie Masson ◽  
Massimiliano Rossi ◽  
Audrey Labalme ◽  
Marianne Till ◽  
Detlef Trost ◽  
...  
Keyword(s):  
Chromosomal Abnormalities ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Clinical Consequence ◽  
Diagnostic Dilemma ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Pathogenic Cnvs ◽  
Standard Karyotype

Chromosomal microarray (CMA) is currently considered as a first-tier test in the genetic assessment of patients presenting with intellectual disability and/or multiple congenital abnormalities. The distinction between pathogenic CNVs, polymorphisms, and variants of unknown significance can be a diagnostic dilemma for cytogeneticists. The size of the CNV has been proposed as a useful criterion. We herein report the characterization of a 13.6-Mb interstitial duplication 20p11.1p12.1, found in a child presenting with mild global developmental delay, by standard karyotype and CMA. Unexpectedly, the same CNV was detected in the patient's mother and pregnant sister, who were healthy. On the basis of these results, an implication of this CNV in the neurological problems observed in the proband was considered to be unlikely. This report underlines the complexity of genetic counseling concerning rare chromosomal abnormalities, when little information is available either in the literature or in international cytogenetic databases.

scholarly journals Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance

2017 ◽  
Vol 23 (21) ◽  
pp. 6733-6743 ◽  
Author(s):  
Amber E. Bannon ◽  
Jason Kent ◽  
Isaac Forquer ◽  
Ajia Town ◽  
Lillian R. Klug ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Subunit A ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

scholarly journals Clinical Application of Chromosomal Microarray Analysis for Fetuses with Craniofacial Malformations

2020 ◽  
Author(s):  
Chenyang Xu ◽  
Yanbao Xiang ◽  
Xueqin Xu ◽  
Lili Zhou ◽  
Huanzheng Li ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Genetic Basis ◽  
Chromosomal Abnormalities ◽  
Chromosome Analysis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Molecular Technique ◽  
Craniofacial Malformations ◽  
Pathogenic Cnvs ◽  
Clinically Significant

Abstract Background This study aimed to evaluate the applicability of chromosomal microarray analysis (CMA) for prenatal diagnosis of craniofacial malformations (CFMs). We also investigated the potential correlations between chromosomal abnormalities and CFMs. To this end, 118 fetuses with CFMs were enrolled in the study and underwent both G-banded chromosome analysis and CMA. Results Of the 118 cases in this study, 39.8% were isolated CFMs (47/118) whereas 60.2% were non-isolated CFMs (71/118). The detection rate of chromosomal abnormalities or submicroscopic chromosomal abnormalities in non-isolated CFM fetuses was significantly higher than that in isolated CFM fetuses (26/71 vs. 7/47, p = 0.01). Compared to the 16 fetuses (16/104; 15.4%) with pathogenic chromosomal abnormalities detected by karyotype analysis, CMA identified a total of 33 fetuses (33/118; 28.0%) with clinically significant findings. These 33 fetuses included cases with aneuploidy abnormalities (14/118; 11.9%), microdeletion/microduplication syndromes (9/118; 7.6%), and other pathogenic CNVs only (10/118; 8.5%). We further explored the CNV/phenotype correlation and found a series of clear or suspected dosage-sensitive CFM genes. Conclusion CMA is a rapid and reliable molecular technique to identify fetal chromosomal aberrations associated with CFMs. Identification of the genetic basis of CFMs contributes to the understanding of their pathogenesis and etiology.

The study of chromosomal abnormalities in fetuses with ultrasound markers and malformations

2020 ◽  
pp. 62-63
Author(s):  
Ю.К. Киевская ◽  
И.В. Канивец ◽  
Д.В. Пьянков
Keyword(s):  
Microarray Analysis ◽  
Congenital Malformations ◽  
Chromosomal Abnormalities ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Snp Microarrays ◽  
Pathogenic Cnvs ◽  
Chromosome Imbalance ◽  
The Moment ◽  
Cytogenetic Methods

Микроделеционные и микродупликационные синдромы выявляются примерно у 8% плодов с врожденными пороками развития (ВПР), однако диагностика патогенных CNVs в пренатальном периоде в данный момент не регламентирована и зачастую основана на технических возможностях лаборатории. Представлены результаты исследования плодов, которые имели ВПР и/или маркеры хромосомной патологии, установленные по УЗИ, методом хромосомного микроматричного анализа (ХМА). В выборке (N=1048) у 10,3% плодов были обнаружены числовые аномалии хромосом и у 7,4% плодов были выявлены патогенные хромосомные аномалии, которые невозможно выявить при стандартном кариотипировани из-за их малого размера. Результаты нашего анализа согласуются с данными литературы, демонстрирующей большую эффективность SNP-микроматриц по сравнению с классическими цитогенетическими методами. Microdeletion and microduplication syndromes are detected in approximately 8% of fetuses with congenital malformations, however, the diagnosis of pathogenic CNVs in the prenatal period, at the moment, is unregulated and often based on the technical capabilities of the laboratory. The thesis presents the result of a study of fetuses that had congenital malformations and / or markers of chromosomal abnormalities, determined by ultrasound, by the method of chromosomal microarray analysis. Using chromosomal microarray analysis in our sample (N = 1048), numerical chromosome abnormalities were detected in 10.3% of the fetuses and pathogenic chromosome imbalance was revealed in 7.4% of the fetuses, which cannot be detected by standard karyotyping. The results of our analysis are consistent with the data of the scientific literature, which demonstrates the greater efficiency of using SNP microarrays in comparison with classical cytogenetic methods.

scholarly journals Functional characterization of variants of unknown significance (VUS) in patients and their responsiveness to targeted therapy drugs (TTD)

2016 ◽  
Vol 27 ◽  
pp. vi403
Author(s):  
G. Tarcic ◽  
C.M. Walko ◽  
H.L. McLeod ◽  
J.K. Hicks ◽  
Z. Barbash ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Functional Characterization ◽  
Variants Of Unknown Significance ◽  
Unknown Significance

scholarly journals Clinical and Genetic Characterization of Craniosynostosis in Saudi Arabia

2021 ◽  
Vol 9 ◽  
Author(s):  
Malak Alghamdi ◽  
Taghreed R. Alhumsi ◽  
Ikhlass Altweijri ◽  
Waleed H. Alkhamis ◽  
Omar Barasain ◽  
...  
Keyword(s):  
Cranial Sutures ◽  
Saudi Population ◽  
Variants Of Unknown Significance ◽  
Patient Demographics ◽  
Genetic Patterns ◽  
Unknown Significance ◽  
Electronic Chart ◽  
Metopic Suture ◽  
Craniofacial Features

Background: Craniosynostosis (CS) is defined as pre-mature fusion of one or more of the cranial sutures. CS is classified surgically as either simple or complex based on the number of cranial sutures involved. CS can also be classified genetically as isolated CS or syndromic CS if the patient has extracranial deformities. Currently, the link between clinical and genetic patterns of CS in the Saudi population is poorly understood.Methodology: We conducted a retrospective cohort study among 28 CS patients, of which 24 were operated and four were not. Clinical and genetic data were collected between February 2015 and February 2019, from consenting patient's families. The electronic chart data were collected and analyzed including patient demographics, craniofacial features, other anomalies and dysmorphic features, operative data, intra cranial pressure (ICP), parent consanguinity and genetic testing results.Results: The most common deformity in our population was trigonocephaly. The most performed procedure was cranial vault reconstruction with fronto-orbital advancement, followed by posterior vault distraction osteogenesis and suturectomy with barrel staving. Genetics analysis revealed pathogenic mutations in FGFR2 (6 cases), TWIST1 (3 cases), ALPL (2 cases), and TCF12 (2 cases), and FREM1 (2 case).Conclusion: Compared to Western countries, our Saudi cohort displays significant differences in the prevalence of CS features, such as the types of sutures and prevalence of inherited CS. The genomic background allows our phenotype-genotype study to reclassify variants of unknown significance. Worldwide, the sagittal suture is the most commonly affected suture in simple CS, but in the Saudi population, the metopic suture fusion was most commonly seen in our clinic. Further studies are needed to investigate the characteristics of CS in our population in a multicenter setting.

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.

Chromosomal microarray findings in pregnancies with an isolated pelvic kidney

2018 ◽  
Vol 47 (1) ◽  
pp. 30-34
Author(s):  
Lena Sagi-Dain ◽  
Amihood Singer ◽  
Ayala Frumkin ◽  
Adel Shalata ◽  
Arie Koifman ◽  
...  
Keyword(s):  
Copy Number ◽  
Risk Estimation ◽  
Copy Number Variants ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Pelvic Kidney ◽  
Local Data ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Clinically Significant

Abstract Objective To examine the risk for abnormal chromosomal microarray analysis (CMA) results among fetuses with an apparently isolated pelvic kidney. Methods Data from all CMA analyses performed due to an isolated pelvic kidney reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained. Risk estimation was performed comparing the rate of abnormal observed CMA findings to the general population risk, based on a systematic review encompassing 9272 cases and on local data of 5541 cases. Results Of 120 pregnancies with an isolated pelvic kidney, two gain-of-copy number variants suggesting microduplication syndromes were demonstrated (1.67%). In addition, three variants of unknown significance were detected (2.5%). Conclusion The risk for clinically significant CMA findings among pregnancies with an isolated single pelvic kidney was not significantly different compared to both control populations. The results of our study question the practice of routine CMA analysis in fetuses with an isolated pelvic kidney.

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