Implementation of High Resolution Whole Genome Array CGH in the Prenatal Clinical Setting: Advantages, Challenges, and Review of the Literature

Evangelidou, Paola; Alexandrou, Angelos; Moutafi, Maria; Ioannides, Marios; Antoniou, Pavlos; Koumbaris, George; Kallikas, Ioannis; Velissariou, Voula; Sismani, Carolina; Patsalis, Philippos C.

doi:10.1155/2013/346762

Cited by 49 publications

(44 citation statements)

References 31 publications

(37 reference statements)

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“…4 ). Molecular karyotyping is blind to both conditions; aCGH can -due to technical issues -detect neither low level mosaic imbalances nor heterochromatic gains of copy numbers [Evangelidou et al, 2013]. Thus, to be able to discover an sSMC in an infertile male, and thus identify the reason for the infertility, chromosome analysis needs to be done.…”

Section: Discussionmentioning

confidence: 99%

Impaired Spermatogenesis due to Small Supernumerary Marker Chromosomes: The Reason for Infertility Is Only Reliably Ascertainable by Cytogenetics

Liehr¹,

Al-Rikabi²

2018

Sex Dev

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Infertile male with small supernumerary marker chromosomes (sSMCs) were studied. Overall, 37 own patients and 166 cases from the literature were included. sSMCs of our own cases were characterized by multicolor-FISH probe sets. Available clinical data of the infertile males were also evaluated, and meta-analysis on suitability of molecular karyotyping for sSMC characterization was done. As a result, sSMCs can be optimally characterized by single-cell directed (molecular) cytogenetics. In infertile males, sSMCs derive predominantly from one of the acrocentric chromosomes, mainly chromosomes 15, 14, and 22. Interestingly, altered spermiograms were found in 62% of the males with an sSMC, while the remainder cases had infertility in connection with recurrent spontaneous abortions. Meta-analysis for detectability of sSMCs by aCGH revealed that 81-87% of the cases would have not been picked up by exclusive use of that approach. Thus, as impaired spermatogenesis is known to be indicative for gross chromosomal anomalies in infertile male patients, it can be concluded from this study that the presence of sSMCs also needs to be considered. However, sSMCs can only be reliably detected by standard karyotyping and not by modern high throughput approaches like aCGH and next-generation sequencing.

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Section: Discussionmentioning

confidence: 99%

Impaired Spermatogenesis due to Small Supernumerary Marker Chromosomes: The Reason for Infertility Is Only Reliably Ascertainable by Cytogenetics

Liehr¹,

Al-Rikabi²

2018

Sex Dev

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“…In general, high-throughput whole genomic testing includes whole genomic aCGH and WES. The former can detect genomic imbalances more effectively than FISH or karyotyping2223, and the latter can detect any SNVs and del/ins in coding sequences across the genome. Compared with candidate gene or gene panel sequencing, WES provides an unbiased approach to affordably screen a patient’s entire exome to establish the genetic basis of disease.…”

Section: Discussionmentioning

confidence: 99%

A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome

Xie

Peng

et al. 2017

Sci Rep

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Cockayne syndrome is an autosomal recessive disorder principally characterized by postnatal growth failure and progressive neurological dysfunction, due primarily to mutations in ERCC6 and ERCC8. Here, we report our diagnostic experience for two patients in a Chinese family suspected on clinical grounds to have Cockayne syndrome. Using multiple molecular techniques, including whole exome sequencing, array comparative genomic hybridization and quantitative polymerase chain reaction, we identified compound heterozygosity for a maternal splicing variant (chr5:60195556, NM_000082:c.618-2A > G) and a paternal complex deletion/inversion/deletion rearrangement removing exon 4 of ERCC8, confirming the suspected pathogenesis in these two subjects. Microhomology (TAA and AGCT) at the breakpoints indicated that microhomology-mediated FoSTeS events were involved in this complex ERCC8 rearrangement. This diagnostic experience illustrates the value of high-throughput genomic technologies combined with detailed phenotypic assessment in clinical genetic diagnosis.

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“…To avoid interpretation problems, these arrays should cover all known pathogenic CNVs and have a low-resolution backbone for the detection of relatively large CNVs thus keeping the detection of CNVs of unclear significance to the minimum 14 . Although the American College of Obstetricians and Gynecologists (ACOG) Bulletin Committee advises to perform a-CGH even in cases with no congenital anomalies seen at ultrasound, critical issues have arisen from this guideline.…”

Section: Which Type Of A-cgh Platform Should Be Developed? Wide Genommentioning

confidence: 99%

Array comparative genomic hybridization (a-CGH): state of the art and perspective

Tonni¹,

Rôlo²,

Júnior³

2014

Rev. Bras. Ginecol. Obstet.

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There is convincing evidence suggesting a potential benefit of chromosomal microarray analysis for fetal abnormalities beyond conventional fetal karyotyping [1][2][3][4][5] . Microarray chromosomal genomic hybridization (a-CGH) may provide submicroscopic rearrangements especially duplicated or deleted portion of the DNA also known as copy number variants (CNVs). A limitation of chromosomal microarray analysis is the potential to identify variants of unknown clinical significance (VOUS). This occurred in 3.4% of cases in the NICHD trial. Such results were classified as "likely benign" in 1.8% of cases and "likely pathogenic" in 1.6% 6 . The result may be uncertain because the CNVs may be rare, novel or characterized by variable penetrance. Furthermore, in such cases, a parental search is mandatory to detect a carrier state or a de novo mutation and to calculate recurrent risk in a genetic counseling. Is genetic counseling advice before testing with a-CGH? Should an informed consent be obtained?Pre as well as post-test genetic counseling is mandatory when karyotyping is performed with a-CGH. Patients must be counseled concerning the incidence of VOUS, identification of diseases with variable clinical presentation, identification of consanguinity and/or non-paternity as well as adult-onset diseases. It is mandatory that healthcare givers do not performed the testing before genetic counseling and signed informed consent. In addition, as the amount of information depends by the type of array technique used and laboratory policy 7 , it is essential that doctors as well as patients be informed about this. Notwithstanding, the NICHD trial have demonstrated that women who received abnormal results reported a need for extensive support and counseling while referring a lack of good understanding of the potential for uncertain results 8 . Is there evidence to indicate that a-CGH should be performed in all cases as integrated prenatal karyotyping testing when fetal malformations are detected on ultrasound?Array chromosomal genomic hybridization (a-CGH) studies performed in fetuses with sonographic anomalies and normal karyotype have demonstrated to detect clinically significant CNVs in 2% of cases 9 . Moreover, when rapid fetal karyotyping is clinically indicated, oligonucleotide a-CGH for direct analysis of uncultured amniocytes has shown to be feasible. The use of oligonucleotide arrays increases the sensitivity and accuracy of detection over previous bacterial artificial chromosome (BAC)-based arrays and shorter reporting time 10 . In a series of 162 fetuses with sonographic anomalies of whom 6.8% had abnormal karyotype and 23.7% had abnormal

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Implementation of High Resolution Whole Genome Array CGH in the Prenatal Clinical Setting: Advantages, Challenges, and Review of the Literature

Cited by 49 publications

References 31 publications

Impaired Spermatogenesis due to Small Supernumerary Marker Chromosomes: The Reason for Infertility Is Only Reliably Ascertainable by Cytogenetics

Impaired Spermatogenesis due to Small Supernumerary Marker Chromosomes: The Reason for Infertility Is Only Reliably Ascertainable by Cytogenetics

A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome

Array comparative genomic hybridization (a-CGH): state of the art and perspective

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