Chromosomal Microarrays and Exome Sequencing for Diagnosis of Fetal Abnormalities

2019 ◽  
pp. 577-595 ◽  
Author(s):  
Brynn Levy ◽  
Melissa Stosic ◽  
Jessica Giordano ◽  
Ronald Wapner
Keyword(s):  
Exome Sequencing ◽  
Fetal Abnormalities ◽  
Chromosomal Microarrays

scholarly journals Diagnosis of fetal abnormalities using exome sequencing: translating research into practice

2020 ◽  
Vol 56 (5) ◽  
pp. 779-779
Author(s):  
E. Dempsey ◽  
J. Pryce ◽  
B. Thilaganathan ◽  
S. Mansour ◽  
T. Homfray ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Fetal Abnormalities

P–546 Exome sequencing and preimplantation genetic testing for unexplained recurrent fetal malformations

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
G Ev. M ◽  
R Morales ◽  
B Lledo ◽  
J A Ortiz ◽  
F M Lozano ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Informed Consent ◽  
Exome Sequencing ◽  
Genetic Counselling ◽  
Blastocyst Stage ◽  
Embryo Biopsy ◽  
Fetal Abnormalities ◽  
New Genes ◽  
Monogenic Diseases ◽  
Fetal Malformations

Abstract Study question Could patient suffering unexplained recurrent fetal malformations be benefit of PGT-M by exome sequencing mutations identification? Summary answer Patients suffering unexplained recurrent fetal malformations could be benefit of the use of exome sequencing in combination to PGT-M to have a healthy live birth. What is known already Fetal malformations account for approximately 3% of live births and causes include: chromosomal abnormalities, exposure to toxic substances or teratogens and infections. Recently, studies have shown that several monogenic diseases are linked to fetal abnormalities. However, because of the large number of potential genes, genetic testing is challenging. Exome sequencing is widely used to detect genetic mutations and has emerged as a useful tool for finding the genetic cause of fetal abnormalities. The aim of this study was to show how exome sequencing in patients suffering unexplained recurrent fetal malformations in combination to PGT-M could lead to successful healthy newborn. Study design, size, duration Case report of a non-consanguineous couple with unexplained, recurrent fetal malformations. Couple were recruited during clinical consultation for unexplained recurrent fetal malformations at a private reproductive medicine clinic. The couple had two malformed fetus with the same congenital abnormalities: hydrocephalus, cerebellar vermis agenesis, cerebellar hypoplasia and enlarged cisterna magna. Patients signed written informed consent regarding to exome testing. For fetal sample, informed consent was obtained from parents. Participants/materials, setting, methods Sample of the affected fetus were provided. Parental genomic DNA was extracted from peripheral blood. Exome sequencing was performed using TrusightOne (Illumina®). FASTAQ data were processed through BWA and GATK algorithm. VCF files were analysed using Variant Interpreter software. After genetic counselling, PGT-M was performed using linkage polymorphic markers analysis and mutation sequencing. Embryo biopsy was carried at blastocyst stage. Embryos were vitrified and one healthy embryo was thaw and transfer in a subsequent cycle. Main results and the role of chance An homozygous novel pathogenic mutation c.641 C>T (p.Ala214Val) in FVLCR2 gene was found. The parents were heterozygous carriers revealing that the detected variant follow an autosomal recessive pattern. The FLVCR2 (14q24.3) gene encodes a transmembrane protein that belongs to the major facilitator superfamily of secondary carriers that transport small solutes in response to chemiosmosis ion gradients, such as calcium. Mutations in this gene are related to fetal central nervous system defects. This disorder is diagnosed prenatally and is lethal. PGT-M was recommended during genetic counselling. After control ovarian stimulation 14 oocytes were retrieved and finally 4 embryos were suitable for embryo biopsy at blastocyst stage. One embryo was diagnosed as healthy, two affected and one heterozygous carrier. The healthy embryo was thaw and transferred and a healthy male baby was born. Limitations, reasons for caution Exome sequencing has technical limitations: only covers mutations in coding regions and does not cover noncoding regions of the genome. It also cannot reliably detect copy-number variants at single gene level. Wider implications of the findings: This study offers strong evidence of exome-sequencing as a new diagnostic strategy and powerful tool discovering the underlying etiology of recurrent fetal malformations and identifying new genes important for human development. Using this strategy in combination with PGT-M, clinicians can help couples with recurrent fetal malformations to have healthy newborns. Trial registration number Not applicable

scholarly journals Preimplantation genetic risk reduction: a new dilemma in the era of chromosomal microarrays and exome sequencing

2015 ◽  
Vol 31 (5) ◽  
pp. 706-710 ◽  
Author(s):  
Gheona Altarescu ◽  
Rachel Beeri ◽  
Galit Lazer-Derbeko ◽  
Talia Eldar-Geva ◽  
Avraham Steinberg ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Risk Reduction ◽  
Genetic Risk ◽  
Chromosomal Microarrays

scholarly journals Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound

2014 ◽  
Vol 23 (12) ◽  
pp. 3269-3277 ◽  
Author(s):  
K. J. Carss ◽  
S. C. Hillman ◽  
V. Parthiban ◽  
D. J. McMullan ◽  
E. R. Maher ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Diagnosis ◽  
Fetal Abnormalities

scholarly journals 2.3 Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound

2014 ◽  
Vol 99 (Suppl 1) ◽  
pp. A1.3-A1
Author(s):  
SC Hillman ◽  
K Carss ◽  
D McMullan ◽  
V Parthiban ◽  
E Maher ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Diagnosis ◽  
Fetal Abnormalities

scholarly journals Update on the use of exome sequencing in the diagnosis of fetal abnormalities

2019 ◽  
Vol 62 (8) ◽  
pp. 103663 ◽  
Author(s):  
Lauren Ferretti ◽  
Rhiannon Mellis ◽  
Lyn S. Chitty
Keyword(s):  
Exome Sequencing ◽  
Fetal Abnormalities

scholarly journals Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes

2021 ◽  
Author(s):  
Mohamed Al-Hamed ◽  
Wesam Kurdi ◽  
Rubina Khan ◽  
Maha Tulbah ◽  
Maha AlNemer ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Microarray Analysis ◽  
Molecular Genetic ◽  
Genetic Diagnostics ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Fetal Anomalies ◽  
Fetal Abnormalities ◽  
Pathogenic Variants ◽  
Structural Anomalies

Abstract Background Fetal abnormalities are detected in 3% of all pregnancies and are responsible for approximately 20% of all perinatal deaths. Chromosomal microarray analysis (CMA) and exome sequencing (ES) are widely used in prenatal settings for molecular genetic diagnostics with variable diagnostic yields. In this study, we aimed to determine the diagnostic yield of trio-ES in detecting the cause of fetal abnormalities within a highly consanguineous population. Methods In families with a history of congenital anomalies, a total of 119 fetuses with structural anomalies were recruited and DNA from invasive samples were used together with parental DNA samples for trio-ES and CMA. Data were analysed to determine possible underlying genetic disorders associated with observed fetal phenotypes. Results The cohort had a known consanguinity of 81%. Trio-ES led to diagnostic molecular genetic findings in 59 fetuses (with pathogenic / likely pathogenic variants) most with multisystem or renal abnormalities. CMA detected chromosomal abnormalities compatible with the fetal phenotype in another 7 cases. Monogenic ciliopathy disorders with an autosomal recessive inheritance were the predominant cause of multisystem fetal anomalies (24/59 cases, 40.7%) with loss of function variants representing the vast majority of molecular genetic abnormalities. Heterozygous de novo pathogenic variants were found in 4 fetuses. A total of 23 novel variants predicted to be associated with the phenotype were detected. Conclusion Prenatal trio-ES and CMA detected likely causative molecular genetic defects in a total of 55% of families with fetal anomalies confirming the diagnostic utility of trio-ES and CMA as first line genetic test in the prenatal diagnosis of multisystem fetal anomalies including ciliopathy syndromes.

scholarly journals A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases

2018 ◽  
Author(s):  
Michelle M. Clark ◽  
Zornitza Stark ◽  
Lauge Farnaes ◽  
Tiong Y. Tan ◽  
Susan M. White ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Clinical Utility ◽  
Meta Analysis ◽  
Genetic Diseases ◽  
Diagnostic Sensitivity ◽  
Whole Genome ◽  
Significant Difference ◽  
Chromosomal Microarrays

AbstractIMPORTANCEGenetic diseases are a leading cause of childhood mortality. Whole genome sequencing (WGS) and whole exome sequencing (WES) are relatively new methods for diagnosing genetic diseases.OBJECTIVESCompare the diagnostic sensitivity (rate of causative, pathogenic or likely pathogenic genotypes in known disease genes) and rate of clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and chromosomal microarrays (CMA) in children with suspected genetic diseases.DATA SOURCES AND STUDY SELECTIONSystematic review of the literature (January 2011 - August 2017) for studies of diagnostic sensitivity and/or clinical utility of WGS, WES, and/or CMA in children with suspected genetic diseases. 2% of identified studies met selection criteria.DATA EXTRACTION AND SYNTHESISTwo investigators extracted data independently following MOOSE/PRISMA guidelines.MAIN OUTCOMES AND MEASURESPooled rates and 95% Cl were estimated with a random-effects model. Metaanalysis of the rate of diagnosis was based on test type, family structure, and site of testing.RESULTSIn 36 observational series and one randomized control trial, comprising 20,068 children, the diagnostic sensitivity of WGS (0.41, 95% Cl 0.34-0.48, I2=44%) and WES (0.35, 95% Cl 0.31-0.39, I2=85%) were qualitatively greater than CMA (0.10, 95% Cl 0.08-0.12, I2=81%). Subgroup meta-analyses showed that the diagnostic sensitivity of WGS was significantly greater than CMA in studies published in 2017 (P<.0001, I2=13% and I2=40%, respectively), and the diagnostic sensitivity of WES was significantly greater than CMA in studies featuring within-cohort comparisons (P<001, I2=36%). Evidence for a significant difference in the diagnostic sensitivity of WGS and WES was lacking. In studies featuring within-cohort comparisons of singleton and trio WGS/WES, the likelihood of diagnosis was significantly greater for trios (odds ratio 2.04, 95% Cl 1.62-2.56, I2=12%; P<.0001). The diagnostic sensitivity of WGS/WES with hospital-based interpretation (0.41, 95% Cl 0.38-0.45, I2=50%) was qualitatively higher than that of reference laboratories (0.28, 95% Cl 0.24-0.32, I2=81%); this difference was significant in meta-analysis of studies published in 2017 (P=.004, I2=34% and I2=26%, respectively). The rates of clinical utility of WGS (0.27, 95% Cl 0.17-0.40, I2=54%) and WES (0.18, 95% Cl 0.13-0.24, I2-77%) were higher than CMA (0.06, 95% Cl 0.05-0.07, I2=42%); this difference was significant in meta-analysis of WGS vs CMA (P<.0001).CONCLUSIONS AND RELEVANCEIn children with suspected genetic diseases, the diagnostic sensitivity and rate of clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic sensitivity were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.Key PointsQuestionWhat is the relative diagnostic sensitivity and clinical utility of different genome tests in children with suspected genetic diseases?FindingsWhole genome sequencing had greater diagnostic sensitivity and clinical utility than chromosomal microarrays. Testing parent-child trios had greater diagnostic sensitivity than proband singletons. Hospital-based testing had greater diagnostic sensitivity than reference laboratories.MeaningTrio genomic sequencing is the most sensitive diagnostic test for children with suspected genetic diseases.

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